ABSTRACT
Monocular deprivation (MD) causes an initial decrease in synaptic responses to the deprived eye in juvenile mouse primary visual cortex (V1) through Hebbian long-term depression (LTD). This is followed by a homeostatic increase, which has been attributed either to synaptic scaling or to a slide threshold for Hebbian long-term potentiation (LTP) rather than scaling. We therefore asked in mice of all sexes whether the homeostatic increase during MD requires GluN2B-containing NMDA receptor activity, which is required to slide the plasticity threshold but not for synaptic scaling. Selective GluN2B blockade from 2-6â d after monocular lid suture prevented the homeostatic increase in miniature excitatory postsynaptic current (mEPSC) amplitude in monocular V1 of acute slices and prevented the increase in visually evoked responses in binocular V1 in vivo. The decrease in mEPSC amplitude and visually evoked responses during the first 2â d of MD also required GluN2B activity. Together, these results support the idea that GluN2B-containing NMDA receptors first play a role in LTD immediately following eye closure and then promote homeostasis during prolonged MD by sliding the plasticity threshold in favor of LTP.
Subject(s)
Dominance, Ocular , Excitatory Postsynaptic Potentials , Mice, Inbred C57BL , Neuronal Plasticity , Receptors, N-Methyl-D-Aspartate , Animals , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Mice , Male , Dominance, Ocular/physiology , Female , Neuronal Plasticity/physiology , Neuronal Plasticity/drug effects , Excitatory Postsynaptic Potentials/physiology , Excitatory Postsynaptic Potentials/drug effects , Evoked Potentials, Visual/physiology , Visual Cortex/physiology , Visual Cortex/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Sensory Deprivation/physiology , Long-Term Potentiation/physiology , Long-Term Potentiation/drug effects , Long-Term Synaptic Depression/physiology , Long-Term Synaptic Depression/drug effects , Photic Stimulation/methodsABSTRACT
N, N-dimethyltryptamine (DMT) is a psychedelic tryptamine acting on 5-HT2A serotonin receptors, which is associated with intense visual hallucinatory phenomena and perceptual changes such as distortions in visual space. The neural underpinnings of these effects remain unknown. We hypothesised that changes in population receptive field (pRF) properties in the primary visual cortex (V1) might underlie visual perceptual experience. We tested this hypothesis using magnetic resonance imaging (MRI) in a within-subject design. We used a technique called pRF mapping, which measures neural population visual response properties and retinotopic maps in early visual areas. We show that in the presence of visual effects, as documented by the Hallucinogen Rating Scale (HRS), the mean pRF sizes in V1 significantly increase in the peripheral visual field for active condition (inhaled DMT) compared to the control. Eye and head movement differences were absent across conditions. This evidence for short-term effects of DMT in pRF may explain perceptual distortions induced by psychedelics such as field blurring, tunnel vision (peripheral vision becoming blurred while central vision remains sharp) and the enlargement of nearby visual space, particularly at the visual locations surrounding the fovea. Our findings are also consistent with a mechanistic framework whereby gain control of ongoing and evoked activity in the visual cortex is controlled by activation of 5-HT2A receptors.
Subject(s)
Hallucinogens , Magnetic Resonance Imaging , Humans , Hallucinogens/pharmacology , Adult , Male , Female , Young Adult , Visual Cortex/drug effects , Visual Cortex/physiology , Visual Cortex/diagnostic imaging , Perceptual Distortion/drug effects , Perceptual Distortion/physiology , N,N-Dimethyltryptamine/pharmacology , Visual Fields/drug effects , Visual Fields/physiology , Visual Perception/drug effects , Visual Perception/physiology , Tryptamines/pharmacology , Primary Visual Cortex/drug effects , Primary Visual Cortex/physiology , Primary Visual Cortex/diagnostic imaging , Brain Mapping/methodsABSTRACT
Abnormal visual experience during the critical period can cause deficits in visual function, such as amblyopia. High magnesium (Mg2+) supplementary can restore ocular dominance (OD) plasticity, which promotes the recovery of amblyopic eye acuity in adults. However, it remains unsolved whether Mg2+ could recover binocular vision in amblyopic adults and what the molecular mechanism is for the recovery. We found that in addition to the recovery of OD plasticity, binocular integration can be restored under the treatment of high Mg2+ in amblyopic mice. Behaviorally, Mg2+-treated amblyopic mice showed better depth perception. Moreover, the effect of high Mg2+ can be suppressed with transient receptor potential melastatin-like 7 (TRPM7) knockdown. Collectively, our results demonstrate that high Mg2+ could restore binocular visual functions from amblyopia. TRPM7 is required for the restoration of plasticity in the visual cortex after high Mg2+ treatment, which can provide possible clinical applications for future research and treatment of amblyopia.
Subject(s)
Amblyopia , Magnesium , Mice, Inbred C57BL , TRPM Cation Channels , Vision, Binocular , Animals , TRPM Cation Channels/metabolism , Amblyopia/physiopathology , Amblyopia/drug therapy , Amblyopia/therapy , Magnesium/pharmacology , Vision, Binocular/physiology , Vision, Binocular/drug effects , Mice , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Male , Recovery of Function/drug effects , Recovery of Function/physiology , Visual Cortex/drug effects , Dominance, Ocular/drug effects , Dominance, Ocular/physiology , FemaleABSTRACT
RATIONALE: Methamphetamine addiction is a persistent and intractable pathological learning and memory, whereas no approved therapeutics is available. However, few attentions have been paid to how associative learning participates in the formation of intractable memory related to drug addiction OBJECTIVES AND METHODS: To investigate the role of associative learning in methamphetamine addiction and the underlying neurobiological mechanism, methamphetamine self-administration, oral sucrose self-administration, chemogenetic neuromanipulation, and fiber photometry in mice were performed in this study. RESULTS: We reported that associative learning increased methamphetamine-induced self-administration, but not oral sucrose self-administration. In addition, the enhancement of methamphetamine-induced self-administration was independent of more methamphetamine consumption, and remained with higher drug-taking and motivation in the absence of visual cues, suggesting the direct effects of the associative learning that enhanced methamphetamine-induced self-administration. Moreover, chemogenetic inactivation of the secondary visual cortex (V2) reduced the enhancement of the drug-taking induced by associative learning but did not alter sucrose-taking. Further fiber photometry of V2 neurons demonstrated that methamphetamine-associative learning elicits V2 neuron excitation, and sucrose-associative learning elicits V2 neuron inhibition. CONCLUSIONS: Therefore, this study reveals the neurobiological mechanism of V2 excitability underlying how associative learning participates in the formation of intractable memory related to drug addiction, and gives evidence to support V2 as a promising target for stimulation therapy for methamphetamine addiction.
Subject(s)
Amphetamine-Related Disorders , Association Learning , Methamphetamine , Mice, Inbred C57BL , Self Administration , Visual Cortex , Animals , Methamphetamine/administration & dosage , Methamphetamine/pharmacology , Mice , Male , Association Learning/drug effects , Association Learning/physiology , Visual Cortex/drug effects , Central Nervous System Stimulants/administration & dosage , Central Nervous System Stimulants/pharmacology , Neurons/drug effectsABSTRACT
Lysergic acid diethylamide (LSD) produces hallucinations, which are perceptions uncoupled from the external environment. How LSD alters neuronal activities in vivo that underlie abnormal perceptions is unknown. Here, we show that when rats run along a familiar track, hippocampal place cells under LSD reduce their firing rates, their directionality, and their interaction with visual cortical neurons. However, both hippocampal and visual cortical neurons temporarily increase firing rates during head-twitching, a behavioral signature of a hallucination-like state in rodents. When rats are immobile on the track, LSD enhances cortical firing synchrony in a state similar to the wakefulness-to-sleep transition, during which the hippocampal-cortical interaction remains dampened while hippocampal awake reactivation is maintained. Our results suggest that LSD suppresses hippocampal-cortical interactions during active behavior and during immobility, leading to internal hippocampal representations that are degraded and isolated from external sensory input. These effects may contribute to LSD-produced abnormal perceptions.
Subject(s)
Hippocampus/drug effects , Lysergic Acid Diethylamide/pharmacology , Visual Cortex/drug effects , Animals , Behavior, Animal/drug effects , CA1 Region, Hippocampal/physiology , Electromyography , Fluorobenzenes/pharmacology , Hippocampus/physiology , Male , Neurons/physiology , Piperidines/pharmacology , Rats , Rats, Long-Evans , Sleep/physiology , Visual Cortex/pathology , Visual Cortex/physiology , Wakefulness/physiologyABSTRACT
People with HIV (PWH) use cannabis at a higher rate than the general population, but the influence on neural activity is not well characterized. Cannabis use among PWH may have a beneficial effect, as neuroinflammation is known to be a critical problem in PWH and cannabis use has been associated with a reduction in proinflammatory markers. Thus, it is important to understand the net impact of cannabis use on brain and cognitive function in PWH. In this study, we collected magnetoencephalographic (MEG) brain imaging data on 81 participants split across four demographically matched groups (i.e., PWH using cannabis, controls using cannabis, non-using PWH, and non-using controls). Participants completed a visuospatial processing task during MEG. Time-frequency resolved voxel time series were extracted to identify the dynamics of oscillatory and pre-stimulus baseline neural activity. Our results indicated strong theta (4-8 Hz), alpha (10-16 Hz), and gamma (62-72 Hz) visual oscillations in parietal-occipital brain regions across all participants. PWH exhibited significant behavioral deficits in visuospatial processing, as well as reduced theta oscillations and elevated pre-stimulus gamma activity in visual cortices, all of which replicate prior work. Strikingly, chronic cannabis use was associated with a significant reduction in pre-stimulus gamma activity in the visual cortices, such that PWH no longer statistically differed from controls. These results provide initial evidence that cannabis use may normalize some neural aberrations in PWH. This study fills an important gap in understanding the impact of cannabis use on brain and cognitive function in PWH.
Subject(s)
Brain Waves , Cannabinoid Receptor Modulators/pharmacology , Cognitive Dysfunction , HIV Infections/complications , Medical Marijuana/pharmacology , Visual Cortex , Visual Perception , Adult , Brain Waves/drug effects , Brain Waves/physiology , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/physiopathology , Female , Humans , Magnetoencephalography , Male , Middle Aged , Visual Cortex/drug effects , Visual Cortex/physiology , Visual Perception/drug effects , Visual Perception/physiologyABSTRACT
Several lines of research suggest that impairments in long-term potentiation (LTP)-like synaptic plasticity might be a key pathophysiological mechanism in schizophrenia (SZ) and bipolar disorder type I (BDI) and II (BDII). Using modulations of visually evoked potentials (VEP) of the electroencephalogram, impaired LTP-like visual cortical plasticity has been implicated in patients with BDII, while there has been conflicting evidence in SZ, a lack of research in BDI, and mixed results regarding associations with symptom severity, mood states, and medication. We measured the VEP of patients with SZ spectrum disorders (n = 31), BDI (n = 34), BDII (n = 33), and other BD spectrum disorders (n = 2), and age-matched healthy control (HC) participants (n = 200) before and after prolonged visual stimulation. Compared to HCs, modulation of VEP component N1b, but not C1 or P1, was impaired both in patients within the SZ spectrum (χâ2 = 35.1, P = 3.1 × 10-9) and BD spectrum (χâ2 = 7.0, P = 8.2 × 10-3), including BDI (χâ2 = 6.4, P = .012), but not BDII (χâ2 = 2.2, P = .14). N1b modulation was also more severely impaired in SZ spectrum than BD spectrum patients (χâ2 = 14.2, P = 1.7 × 10-4). N1b modulation was not significantly associated with Positive and Negative Syndrome Scale (PANSS) negative or positive symptoms scores, number of psychotic episodes, Montgomery and Åsberg Depression Rating Scale (MADRS) scores, or Young Mania Rating Scale (YMRS) scores after multiple comparison correction, although a nominal association was observed between N1b modulation and PANSS negative symptoms scores among SZ spectrum patients. These results suggest that LTP-like plasticity is impaired in SZ and BD. Adding to previous genetic, pharmacological, and electrophysiological evidence, these results implicate aberrant synaptic plasticity as a mechanism underlying SZ and BD.
Subject(s)
Bipolar Disorder/physiopathology , Cyclothymic Disorder/physiopathology , Evoked Potentials, Visual/physiology , Neuronal Plasticity/physiology , Psychotic Disorders/physiopathology , Schizophrenia/physiopathology , Visual Cortex/physiopathology , Adolescent , Adult , Aged , Anticonvulsants/pharmacology , Antipsychotic Agents/pharmacology , Bipolar Disorder/drug therapy , Cyclothymic Disorder/drug therapy , Electroencephalography , Evoked Potentials, Visual/drug effects , Female , Humans , Male , Middle Aged , Neuronal Plasticity/drug effects , Psychotic Disorders/drug therapy , Schizophrenia/drug therapy , Visual Cortex/drug effects , Young AdultABSTRACT
Context affects the salience and visibility of image elements in visual scenes. Collinear flankers can enhance or decrease the perceptual and neuronal sensitivity to flanked stimuli. These effects are mediated through lateral interactions between neurons in the primary visual cortex (area V1), in conjunction with feedback from higher visual areas. The strength of lateral interactions is affected by cholinergic neuromodulation. Blockade of muscarinic receptors should increase the strength of lateral intracortical interactions, while nicotinic blockade should reduce thalamocortical feed-forward drive. Here we test this proposal through local iontophoretic application of the muscarinic receptor antagonist scopolamine and the nicotinic receptor antagonist mecamylamine, while recording single cells in parafoveal representations in awake fixating macaque V1. Collinear flankers generally reduced neuronal contrast sensitivity. Muscarinic and nicotinic receptor blockade equally reduced neuronal contrast sensitivity. Contrary to our hypothesis, flanker interactions were not systematically affected by either receptor blockade.
Subject(s)
Contrast Sensitivity/physiology , Muscarinic Antagonists/pharmacology , Neurons/physiology , Nicotinic Antagonists/pharmacology , Receptors, Muscarinic/metabolism , Receptors, Nicotinic/metabolism , Visual Cortex/physiology , Animals , Contrast Sensitivity/drug effects , Macaca mulatta , Male , Neurons/drug effects , Photic Stimulation , Receptors, Muscarinic/chemistry , Receptors, Nicotinic/chemistry , Visual Cortex/drug effectsABSTRACT
BACKGROUND: Attentional modulation in the visual cortex of primates is characterized by multiplicative changes of sensory responses with changes in the attentional state of the animal. The cholinergic system has been linked to such gain changes in V1. Here, we aim to determine if a similar link exists in macaque area MT. While rhesus monkeys performed a top-down spatial attention task, we locally injected a cholinergic agonist or antagonist and recorded single-cell activity. RESULTS: Although we confirmed cholinergic influences on sensory responses, there was no additional cholinergic effect on the attentional gain changes. Neither a muscarinic blockage nor a local increase in acetylcholine led to a significant change in the magnitude of spatial attention effects on firing rates. CONCLUSIONS: This suggests that the cellular mechanisms of attentional modulation in the extrastriate cortex cannot be directly inferred from those in the primary visual cortex.
Subject(s)
Attention/physiology , Cholinergic Agonists/pharmacology , Cholinergic Antagonists/pharmacology , Macaca mulatta/physiology , Visual Cortex/physiology , Visual Perception/physiology , Acetylcholine/pharmacology , Animals , Attention/drug effects , Male , Mecamylamine/pharmacology , Scopolamine/pharmacology , Visual Cortex/drug effects , Visual Perception/drug effectsABSTRACT
The aim of this study was to investigate the effect of acute dopamine agonistic and antagonistic manipulation on the visual-cue induced blood oxygen level-dependent signal response in healthy volunteers. Seventeen healthy volunteers in a double-blind placebo-controlled cross-over design received either a dopamine antagonist, agonist or placebo and underwent functional magnetic resonance imaging. Using classical inference and Bayesian statistics, we found no effect of dopaminergic modulation on properties of visual-cue induced blood oxygen level-dependent signals in the visual cortex, particularly on distinct properties of the haemodynamic response function (amplitude, time-to-peak and width). Dopamine-related effects modulating the neurovascular coupling in the visual cortex might be negligible when measured via functional magnetic resonance imaging.
Subject(s)
Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Hemodynamics/drug effects , Magnetic Resonance Imaging/methods , Visual Cortex , Adult , Cross-Over Studies , Cues , Dopamine Agents/pharmacology , Double-Blind Method , Female , Healthy Volunteers , Humans , Male , Neurotransmitter Agents/pharmacology , Photic Stimulation/methods , Visual Cortex/blood supply , Visual Cortex/diagnostic imaging , Visual Cortex/drug effectsABSTRACT
Microglia have crucial roles in sculpting synapses and maintaining neural circuits during development. To test the hypothesis that microglia continue to regulate neural circuit connectivity in adult brain, we have investigated the effects of chronic microglial depletion, via CSF1R inhibition, on synaptic connectivity in the visual cortex in adult mice of both sexes. We find that the absence of microglia dramatically increases both excitatory and inhibitory synaptic connections to excitatory cortical neurons assessed with functional circuit mapping experiments in acutely prepared adult brain slices. Microglia depletion leads to increased densities and intensities of perineuronal nets. Furthermore, in vivo calcium imaging across large populations of visual cortical neurons reveals enhanced neural activities of both excitatory neurons and parvalbumin-expressing interneurons in the visual cortex following microglia depletion. These changes recover following adult microglia repopulation. In summary, our new results demonstrate a prominent role of microglia in sculpting neuronal circuit connectivity and regulating subsequent functional activity in adult cortex.SIGNIFICANCE STATEMENT Microglia are the primary immune cell of the brain, but recent evidence supports that microglia play an important role in synaptic sculpting during development. However, it remains unknown whether and how microglia regulate synaptic connectivity in adult brain. Our present work shows chronic microglia depletion in adult visual cortex induces robust increases in perineuronal nets, and enhances local excitatory and inhibitory circuit connectivity to excitatory neurons. Microglia depletion increases in vivo neural activities of both excitatory neurons and parvalbumin inhibitory neurons. Our new results reveal new potential avenues to modulate adult neural plasticity by microglia manipulation to better treat brain disorders, such as Alzheimer's disease.
Subject(s)
Microglia/metabolism , Nerve Net/metabolism , Photic Stimulation/methods , Visual Cortex/metabolism , Aminopyridines/pharmacology , Animals , Female , Male , Mice , Microglia/chemistry , Microglia/drug effects , Nerve Net/chemistry , Nerve Net/drug effects , Pyrroles/pharmacology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Visual Cortex/chemistry , Visual Cortex/drug effectsABSTRACT
The functional characteristics of the mouse visual system have not previously been well explored using fMRI. In this research, we examined 9.4 T BOLD fMRI responses to visual stimuli of varying pulse durations (1 - 50 ms) and temporal frequencies (1 - 10 Hz) under ketamine and xylazine anesthesia, and compared fMRI responses of anesthetized and awake mice. Under anesthesia, significant positive BOLD responses were detected bilaterally in the major structures of the visual pathways, including the dorsal lateral geniculate nuclei, superior colliculus, lateral posterior nucleus of thalamus, primary visual area, and higher-order visual area. BOLD responses increased slightly with pulse duration, were maximal at 3 - 5 Hz stimulation, and significantly decreased at 10 Hz, which were all consistent with previous neurophysiological findings. When the mice were awake, the BOLD fMRI response was faster in all active regions and stronger in the subcortical areas compared with the anesthesia condition. In the V1, the BOLD response was biphasic for 5 Hz stimulation and negative for 10 Hz stimulation under wakefulness, whereas prolonged positive BOLD responses were observed at both frequencies under anesthesia. Unexpected activation was detected in the extrastriate postrhinal area and non-visual subiculum complex under anesthesia, but not under wakefulness. Widespread positive BOLD activity under anesthesia likely results from the disinhibition and sensitization of excitatory neurons induced by ketamine. Overall, fMRI can be a viable tool for mapping brain-wide functional networks.
Subject(s)
Anesthetics, Dissociative/pharmacology , Brain/diagnostic imaging , Ketamine/pharmacology , Visual Pathways/diagnostic imaging , Wakefulness/physiology , Anesthesia , Animals , Brain/drug effects , Magnetic Resonance Imaging , Male , Mice , Photic Stimulation , Visual Cortex/diagnostic imaging , Visual Cortex/drug effects , Visual Pathways/drug effectsABSTRACT
Our recent report demonstrated that hesperetin (Hst) as a citrus flavonoid, significantly reduces the levels of demyelination in optic chiasm of rats. Previous evidence also indicated that nano-hesperetin (nano-Hst) possesses beneficial impacts in experimental models of Alzheimer's disease and autism. In this study, the effects of nano-Hst on latency of visual signals, demyelination levels, glial activation, and expression of Olig2 and MBP were evaluated in lysolecithin (LPC)-induced demyelination model. Focal demyelination was induced by injection of LPC (1%, 2 µL) into the rat optic chiasm. Animals received oral administration of nano-Hst at dose of 20 mg/kg for 14 or 21 days post LPC injection. Visual evoked potential (VEP) recording showed that nano-Hst reduces the latency of visual signals and ameliorates the extent of demyelination areas and glial activation. Expression levels of the Olig2 and MBP were also significantly increased in nano-Hst treated rats. Overall, our data suggest that nano-Hst reduces the latency of visual signals through its protective effects on myelin sheath, amelioration of glial activation, and enhancement of endogenous remyelination.
Subject(s)
Demyelinating Diseases/drug therapy , Hesperidin/pharmacology , Optic Chiasm/drug effects , Recovery of Function/drug effects , Remyelination/drug effects , Visual Pathways/drug effects , Animals , Demyelinating Diseases/physiopathology , Disease Models, Animal , Evoked Potentials, Visual/drug effects , Evoked Potentials, Visual/physiology , Hesperidin/therapeutic use , Male , Optic Chiasm/physiopathology , Rats , Rats, Wistar , Visual Cortex/drug effects , Visual Cortex/physiopathology , Visual Pathways/physiopathologyABSTRACT
OBJECTIVE: We previously showed that MELAS patients have decreased cerebrovascular reactivity (CVR) (p≤ 0.002) and increased cerebral blood flow (CBF) (p<0.0026); changes correlated with disease severity and % mutant mtDNA (inversely for CVR; directly for CBF). We ran a prospective pilot in 3 MELAS sibs (m.3243A>G tRNALeu(UUR)) with variable % mutant blood mtDNA to assess effects of L-Arginine (L-Arg) (single dose and 6-wk steady-state trial) on regional CBF, arterial CVR and neurovascular coupling. METHODS: Patients were studied with 3T MRI using arterial spin labeling (ASL) to measure CBF and changes in % Blood Oxygen Level Dependent (BOLD) signal to changes in arterial partial pressure of CO2 to measure CVR. Task fMRI consisted of an alternating black and white checkerboard to evaluate visual cortex response in MELAS and controls. RESULTS: Following L-Arg, there was restoration of serum Arg (76-230 µM) in MELAS sibs and a trend towards increasing CVR in frontal and corresponding decrease in occipital cortex; CVR was unchanged globally. There was a 29-37% reduction in baseline CBF in one patient following 6 wks of L-Arg. Pre-treatment fMRI activation in response to visual cortex stimulus was markedly decreased in the same patient compared to controls in primary visual striate cortex V1 and extrastriate regions V2 to V5 with a marked increase toward control values following a single dose and 6 wks of L-Arg. CONCLUSION: Proposed "healing" effect may be due to more efficient utilization of energy substrates with increased cellular energy balances and ensuing reduction in signalling pathways that augment flow in the untreated state. CLASSIFICATION OF EVIDENCE: This prospective pilot study provides Class III evidence that oral L-Arginine (100 mg/kg single dose or 100 mg/kg three times daily po X 6 weeks) normalizes resting blood flow from elevated pre-treatment levels in patients with MELAS syndrome, selectively increases their CVR from reduced pre-treatment levels in regions most impaired at the expense of less abnormal regions, and normalizes reduced BOLD fMRI activation in response to visual cortex stimulus. CLINICAL TRIALS.GOV (NIH): NCT01603446.
Subject(s)
Arginine/therapeutic use , Cerebrovascular Circulation/physiology , MELAS Syndrome/drug therapy , Neurovascular Coupling/physiology , Administration, Oral , Adolescent , Arginine/blood , Arginine/pharmacology , Brain/blood supply , Brain/diagnostic imaging , Brain Mapping , Carbon Dioxide/blood , Cerebrovascular Circulation/drug effects , Female , Humans , Magnetic Resonance Imaging , Male , Neurovascular Coupling/drug effects , Ornithine/blood , Oxygen/blood , Pilot Projects , Prospective Studies , Treatment Outcome , Visual Cortex/drug effects , Young AdultABSTRACT
Functional ultrasound (fUS) is a new tool enabling the imaging of brain activity through the regional monitoring of cerebral blood volume (CBV) dynamics. This innovative technique has not yet demonstrated its full potential in pharmacological applications and drug development. In the current proof-of-concept study, the impact of atomoxetine (ATX), a potent norepinephrine reuptake inhibitor and non-stimulant treatment marketed in attention-deficit/hyperactivity-disorder, was evaluated in anesthetized rat using pharmacological functional ultrasound (pharmaco-fUS) at increasing doses (0.3, 1 and 3 mg/kg). Using regions of interest (acute changes of CBV and functional connectivity) or pixel-based (general linear modeling and independent component analysis) analysis, we here demonstrated that ATX consistently displayed a hemodynamic effect in the visual cortex, the dentate gyrus and thalamus, especially visual areas such as lateral posterior thalamic nuclei and lateral geniculate nuclei (LGN). The time profile of ATX effects was dose-dependent, with fastest CBV increases at the highest dose, and longer CBV increases at the intermediate dose. Standardizing the use of pharmaco-fUS could improve our understanding of the mechanism of action of drugs active in the brain and might constitute a new step to move forward in drug development for neurological disorders.
Subject(s)
Adrenergic Uptake Inhibitors/metabolism , Atomoxetine Hydrochloride/metabolism , Dentate Gyrus/metabolism , Thalamus/metabolism , Ultrasonography/methods , Visual Cortex/metabolism , Adrenergic Uptake Inhibitors/pharmacology , Animals , Atomoxetine Hydrochloride/pharmacology , Dentate Gyrus/diagnostic imaging , Dentate Gyrus/drug effects , Male , Rats , Rats, Inbred WKY , Thalamus/diagnostic imaging , Thalamus/drug effects , Visual Cortex/diagnostic imaging , Visual Cortex/drug effectsABSTRACT
Subanesthetic ketamine evokes rapid and long-lasting antidepressant effects in human patients. The mechanism for ketamine's effects remains elusive, but ketamine may broadly modulate brain plasticity processes. We show that single-dose ketamine reactivates adult mouse visual cortical plasticity and promotes functional recovery of visual acuity defects from amblyopia. Ketamine specifically induces downregulation of neuregulin-1 (NRG1) expression in parvalbumin-expressing (PV) inhibitory neurons in mouse visual cortex. NRG1 downregulation in PV neurons co-tracks both the fast onset and sustained decreases in synaptic inhibition to excitatory neurons, along with reduced synaptic excitation to PV neurons in vitro and in vivo following a single ketamine treatment. These effects are blocked by exogenous NRG1 as well as PV targeted receptor knockout. Thus, ketamine reactivation of adult visual cortical plasticity is mediated through rapid and sustained cortical disinhibition via downregulation of PV-specific NRG1 signaling. Our findings reveal the neural plasticity-based mechanism for ketamine-mediated functional recovery from adult amblyopia.
Subject(s)
Amblyopia/drug therapy , Excitatory Amino Acid Antagonists/pharmacology , Ketamine/pharmacology , Neuregulin-1/metabolism , Neuronal Plasticity/drug effects , Parvalbumins/metabolism , Visual Cortex/drug effects , Amblyopia/metabolism , Amblyopia/pathology , Animals , Female , Male , Mice , Neuregulin-1/genetics , Neurons/drug effects , Neurons/pathology , Synapses/drug effects , Synapses/pathology , Visual Cortex/pathologyABSTRACT
Inherited retinal dystrophies and late-stage age-related macular degeneration, for which treatments remain limited, are among the most prevalent causes of legal blindness. Retinal prostheses have been developed to stimulate the inner retinal network; however, lack of sensitivity and resolution, and the need for wiring or external cameras, have limited their application. Here we show that conjugated polymer nanoparticles (P3HT NPs) mediate light-evoked stimulation of retinal neurons and persistently rescue visual functions when subretinally injected in a rat model of retinitis pigmentosa. P3HT NPs spread out over the entire subretinal space and promote light-dependent activation of spared inner retinal neurons, recovering subcortical, cortical and behavioural visual responses in the absence of trophic effects or retinal inflammation. By conferring sustained light sensitivity to degenerate retinas after a single injection, and with the potential for high spatial resolution, P3HT NPs provide a new avenue in retinal prosthetics with potential applications not only in retinitis pigmentosa, but also in age-related macular degeneration.
Subject(s)
Quantum Dots , Retina/drug effects , Retinitis Pigmentosa/metabolism , Animals , Disease Models, Animal , Female , Injections, Intraocular , Male , Photic Stimulation , Polymers/administration & dosage , Polymers/pharmacology , Quantum Dots/administration & dosage , Quantum Dots/therapeutic use , Rats , Rats, Sprague-Dawley , Visual Cortex/drug effects , Visual Cortex/metabolism , Visual ProsthesisABSTRACT
Mercury (Hg) is an environmental contaminant that poses great risk to human health. However, it is still widely used in artisanal gold-mining enterprises around the world, especially in developing countries. Methylmercury (MeHg) is produced environmentally by biomethylation of inorganic Hg present in water sediments, leading to its subsequent accumulation in the aquatic food chain. Due to its high metabolic rate, the Central Nervous System (CNS) is one of the main targets of MeHg. In the present study, we investigate the impact of chronic MeHg intoxication on NADPH diaphorase (NADPH-d) activity and astrocyte mobilization in the visual cortex of the rat. After 60 days of MeHg administration by oral gavage (0.04 mg/kg/day), tissue samples containing the visual cortex were submitted to measurements of Hg levels, NADPH-d activity, and GFAP immunohistochemistry for identification of astrocytes. MeHg intoxication was associated with increased Hg deposits and with reduced NADPH-d neuropil reactivity in the visual cortex. A morphometric analysis suggested that NADPH-d-positive neurons were mostly spared from MeHg harmful action and intoxicated animals had astrocytic activation similar to the control group. The decrease in NADPH-d neuropil reactivity may be due to the negative effect of chronic MeHg poisoning on both the synthesis and transport of this enzyme in afferent pathways to the visual cortex. The relative resistance of NADPH-d-reactive neurons to chronic MeHg intoxication may be associated with peculiarities in cell metabolism or to a protective role of nitric oxide, safeguarding those neurons from Hg deleterious effects.
Subject(s)
Astrocytes/drug effects , Environmental Pollutants/toxicity , Methylmercury Compounds/toxicity , NADPH Dehydrogenase/metabolism , Neurons/drug effects , Visual Cortex/drug effects , Animals , Astrocytes/enzymology , Behavior, Animal/drug effects , Environmental Pollutants/metabolism , Gold , Humans , Male , Methylmercury Compounds/metabolism , Mining , Neurons/enzymology , Rats , Rats, Wistar , Visual Cortex/enzymology , Visual Cortex/pathologyABSTRACT
Neuromodulatory systems are essential for remodeling glutamatergic connectivity during experience-dependent cortical plasticity. This permissive/enabling function of neuromodulators has been associated with their capacity to facilitate the induction of Hebbian forms of long-term potentiation (LTP) and depression (LTD) by affecting cellular and network excitability. In vitro studies indicate that neuromodulators also affect the expression of Hebbian plasticity in a pull-push manner: receptors coupled to the G-protein Gs promote the expression of LTP at the expense of LTD, and Gq-coupled receptors promote LTD at the expense of LTP. Here we show that pull-push mechanisms can be recruited in vivo by pairing brief monocular stimulation with pharmacological or chemogenetical activation of Gs- or Gq-coupled receptors to respectively enhance or reduce neuronal responses in primary visual cortex. These changes were stable, inducible in adults after the termination of the critical period for ocular dominance plasticity, and can rescue deficits induced by prolonged monocular deprivation.
Subject(s)
Dominance, Ocular/physiology , Long-Term Potentiation/physiology , Neuronal Plasticity/physiology , Neurotransmitter Agents/agonists , Receptors, G-Protein-Coupled/agonists , Visual Cortex/physiology , Animals , Dominance, Ocular/drug effects , Female , Long-Term Potentiation/drug effects , Male , Mice , Mice, Inbred C57BL , Neuronal Plasticity/drug effects , Neurons/drug effects , Neurons/physiology , Neurosciences , Norepinephrine/administration & dosage , Photic Stimulation , Serotonin/administration & dosage , Vision, Monocular/drug effects , Vision, Monocular/physiology , Visual Cortex/drug effectsABSTRACT
In order to characterize the mechanisms controlling plasticity in the mouse visual cortex, we used, for the first time on brain samples, an unconventional proteomic approach to separate acid-extracted proteins by bi-dimensional electrophoresis (AUT/SDS or AUT/AU gels). The analysis was performed on high plasticity critical period young vs. low plasticity adult, and on fluoxetine-induced high plasticity vs. low plasticity untreated adult mice. Mass spectrometry allowed for the identification of 11 proteins that are differentially expressed between critical period and adult mice, and 5 between fluoxetine-treated and control adult mice. We then focused on cofilin 1, as the intensity level of the corresponding spot on 2D gels was higher in both high plasticity conditions. Western blot showed that cofilin 1 expression is dynamically regulated during postnatal life, reaching a peak at the critical period, and decreasing at adult stage, and that it increases in fluoxetine-treated vs. untreated adult mice. In summary, by using a 2D gel electrophoresis differential approach on basic proteins followed by mass spectrometry and immunoblot analysis, we identified cofilin 1 as a potential candidate controlling plasticity levels of the mouse visual cortex.