ABSTRACT
The role of experience in the organization of cortical feedback (FB) remains unknown. We measured the effects of manipulating visual experience on the retinotopic specificity of supragranular and infragranular projections from the lateromedial (LM) visual area to layer (L)1 of the mouse primary visual cortex (V1). LM inputs were, on average, retinotopically matched with V1 neurons in normally and dark-reared mice, but visual exposure reduced the fraction of spatially overlapping inputs to V1. FB inputs from L5 conveyed more surround information to V1 than those from L2/3. The organization of LM inputs from L5 depended on their orientation preference and was disrupted by dark rearing. These observations were recapitulated by a model where visual experience minimizes receptive field overlap between LM inputs and V1 neurons. Our results provide a mechanism for the dependency of surround modulations on visual experience and suggest how expected interarea coactivation patterns are learned in cortical circuits.
ABSTRACT
A prevailing hypothesis is that neurofibrillary tangles play a causal role in driving cognitive decline in Alzheimer's disease (AD) because tangles correlate anatomically with areas that undergo neuronal loss. We used two-photon longitudinal imaging to directly test this hypothesis and observed the fate of individual neurons in two mouse models. At any time point, neurons without tangles died at >3 times the rate as neurons with tangles. Additionally, prior to dying, they became >20% more distant from neighboring neurons across imaging sessions. Similar microstructural changes were evident in a population of non-tangle-bearing neurons in Alzheimer's donor tissues. Together, these data suggest that nonfibrillar tau puts neurons at high risk of death, and surprisingly, the presence of a tangle reduces this risk. Moreover, cortical microstructure changes appear to be a better predictor of imminent cell death than tangle status is and a promising tool for identifying dying neurons in Alzheimer's.
Subject(s)
Alzheimer Disease , Cell Death , Neurofibrillary Tangles , Neurons , Animals , Alzheimer Disease/pathology , Neurofibrillary Tangles/pathology , Neurons/pathology , Neurons/metabolism , Mice , Humans , tau Proteins/metabolism , Disease Models, Animal , Mice, Transgenic , Male , FemaleABSTRACT
The perivascular space (PVS) surrounds cerebral blood vessels and plays an important role in clearing waste products from the brain. Their anatomy and function have been described for arteries, but PVS around veins remain poorly characterized. Using in vivo 2-photon imaging in mice, we determined the size of the PVS around arteries and veins, and their connection with the subarachnoid space. After infusion of 70 kD FITC-dextran into the cerebrospinal fluid via the cisterna magna, labeled PVS were evident around arteries, but veins showed less frequent labeling of the PVS. The size of the PVS correlated with blood vessel size for both pial arteries and veins, but not for penetrating vessels. The PVS around pial arteries and veins was separated from the subarachnoid space by a thin meningeal layer, which did not form a barrier for the tracer. In vivo, FITC-dextran signal was observed adjacent to the vessel wall, but minimally within the wall itself. Post-mortem, there was a significant shift in the tracer's location within the arterial wall, extending into the smooth muscle layer. Taken together, these findings suggest that the PVS around veins has a limited role in the exchange of solutes between CSF and brain parenchyma.
Subject(s)
Brain , Cerebral Arteries , Animals , Mice , Brain/blood supply , Cerebral Arteries/anatomy & histology , Glymphatic System , Fluorescein-5-isothiocyanate/analogs & derivatives , Dextrans , Male , Cerebral Veins/anatomy & histology , Mice, Inbred C57BL , Subarachnoid SpaceABSTRACT
Object recognition often involves the brain segregating objects from their surroundings. Neurophysiological studies of figure-ground texture segregation have yielded inconsistent results, particularly on whether V1 neurons can perform figure-ground texture segregation or just detect texture borders. To address this issue from a population perspective, we utilized two-photon calcium imaging to simultaneously record the responses of large samples of V1 and V4 neurons to figure-ground texture stimuli in awake, fixating macaques. The average response changes indicate that V1 neurons mainly detect texture borders, while V4 neurons are involved in figure-ground segregation. However, population analysis (SVM decoding of PCA-transformed neuronal responses) reveal that V1 neurons not only detect figure-ground borders, but also contribute to figure-ground texture segregation, although requiring substantially more principal components than V4 neurons to reach a 75â¯% decoding accuracy. Individually, V1/V4 neurons showing larger (negative/positive) figure-ground response differences contribute more to figure-ground segregation. But for V1 neurons, the contribution becomes significant only when many principal components are considered. We conclude that V1 neurons participate in figure-ground segregation primarily by defining the figure borders, and the poorly structured figure-ground information V1 neurons carry could be further utilized by V4 neurons to accomplish figure-ground segregation.
ABSTRACT
Cells need to migrate along gradients of chemicals (chemotaxis) in the course of development, wound healing, or immune responses. Neutrophils are prototypical migratory cells that are rapidly recruited to injured or infected tissues from the bloodstream. Their chemotaxis to these inflammatory sites involves changes in cytoskeletal dynamics in response to gradients of chemicals produced therein. Neutrophil chemotaxis has been largely studied in vitro; few assays have been developed to monitor gradient responses in complex living tissues. Here, we describe a laser-wound assay to generate focal injury in zebrafish larvae and monitor changes in behaviour and cytoskeletal dynamics. The first step is to cross adult fish and collect and rear embryos expressing a relevant fluorescent reporter (for example, Lifeact-mRuby, which labels dynamic actin) to an early larval stage. Subsequently, larvae are mounted and prepared for live imaging and wounding under a two-photon microscope. Finally, the resulting data are processed and used for cell segmentation and quantification of actin dynamics. Altogether, this assay allows the visualisation of cellular dynamics in response to acute injury at high resolution and can be combined with other manipulations, such as genetic or chemical perturbations. Key features ⢠This protocol is designed to trigger laser wound in zebrafish larvae using two-photon intravital microscopy. ⢠The ability to wound while imaging makes it possible to monitor the behaviour and actin changes of the cells immediately after gradient exposure. ⢠The protocol requires a two-photon microscope for best results. Compared with one-photon laser wounding, the injury is more precise and has better tissue penetration. ⢠The focal nature of the wounds is suitable for studies of neutrophil swarming/aggregation and can be further adapted to infectious settings.
ABSTRACT
Fatty acid amide hydrolase (FAAH) plays a crucial role in the metabolism of the endocannabinoid system by hydrolyzing a series of bioactive amides, whose abnormal levels are associated with neuronal disorders including Alzheimer's disease (AD). However, due to the lack of suitable quantitative sensing tools, real-time and accurate monitoring of the activity of FAAH in living systems remains unresolved. Herein, a novel enzyme-activated near-infrared two-photon ratiometric fluorescent probe (CANP) based on a naphthylvinylpyridine monofluorophore is successfully developed, in which the electron-withdrawing amide moiety is prone to be hydrolyzed to an electron-donating amine group under the catalysis of FAAH, leading to the activation of the intramolecular charge transfer process and the emergence of a new 80 nm red-shifted emission, thereby achieving a ratiometric luminescence response. Benefiting from the high selectivity, high sensitivity, and ratiometric response to FAAH, the probe CANP is successfully used to quantitatively monitor and image the FAAH levels in living neurons, by which an amyloid ß (Aß)-induced upregulation of endogenous FAAH activity is observed. Similar increases in FAAH activity are found in various brain regions of AD model mice, indicating a potential fatty acid amide metabolite-involved pathway for the pathological deterioration of AD. Moreover, our quantitative FAAH inhibition experiments further demonstrate the great value of CANP as an efficient visual probe for in situ and precise assessment of FAAH inhibitors in complex living systems, assisting the discovery of FAAH-related therapeutic agents.
Subject(s)
Amidohydrolases , Brain , Fluorescent Dyes , Neurons , Amidohydrolases/metabolism , Animals , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Brain/diagnostic imaging , Brain/metabolism , Neurons/metabolism , Mice , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/analysis , Humans , Pyridines/chemistry , Alzheimer Disease/metabolism , Alzheimer Disease/diagnostic imaging , PhotonsABSTRACT
How newly formed memories are preserved while brain plasticity is ongoing has been a source of debate. One idea is that synapses which experienced recent plasticity become resistant to further plasticity, a type of metaplasticity often referred to as saturation. Here, we probe the local dendritic mechanisms that limit plasticity at recently potentiated synapses. We show that recently potentiated individual synapses exhibit a synapse-specific refractory period for further potentiation. We further found that the refractory period is associated with reduced postsynaptic CaMKII signaling; however, stronger synaptic activation only partially restored the ability for further plasticity. Importantly, the refractory period is released after one hour, a timing that coincides with the enrichment of several postsynaptic proteins to pre-plasticity levels. Notably, increasing the level of the postsynaptic scaffolding protein, PSD95, but not of PSD93, overcomes the refractory period. Our results support a model in which potentiation at a single synapse is sufficient to initiate a synapse-specific refractory period that persists until key postsynaptic proteins regain their steady-state synaptic levels.
ABSTRACT
Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with electrophysiological and optical imaging tools during sleep-wake cycles. We found that the activity of major glutamatergic cell populations in the DG is organized into in-fraslow oscillations (0.01 - 0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep. Further experiments revealed that the infraslow oscillation in the DG is modulated by rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by 5-HT1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.
ABSTRACT
In classical cerebellar learning, Purkinje cells (PkCs) associate climbing fiber (CF) error signals with predictive granule cells (GrCs) that were active just prior (â¼150 ms). The cerebellum also contributes to behaviors characterized by longer timescales. To investigate how GrC-CF-PkC circuits might learn seconds-long predictions, we imaged simultaneous GrC-CF activity over days of forelimb operant conditioning for delayed water reward. As mice learned reward timing, numerous GrCs developed anticipatory activity ramping at different rates until reward delivery, followed by widespread time-locked CF spiking. Relearning longer delays further lengthened GrC activations. We computed CF-dependent GrCâPkC plasticity rules, demonstrating that reward-evoked CF spikes sufficed to grade many GrC synapses by anticipatory timing. We predicted and confirmed that PkCs could thereby continuously ramp across seconds-long intervals from movement to reward. Learning thus leads to new GrC temporal bases linking predictors to remote CF reward signals-a strategy well suited for learning to track the long intervals common in cognitive domains.
Subject(s)
Cerebellum , Learning , Purkinje Cells , Reward , Animals , Cerebellum/physiology , Cerebellum/cytology , Mice , Purkinje Cells/physiology , Learning/physiology , Conditioning, Operant/physiology , Male , Mice, Inbred C57BL , Nerve Fibers/physiology , Neuronal Plasticity/physiology , Neurons/physiology , Time Factors , Action Potentials/physiologyABSTRACT
Neurons in the primary cortex carry sensory- and behavior-related information, but it remains an open question how this information emerges and intersects together during learning. Current evidence points to two possible learning-related changes: sensory information increases in the primary cortex or sensory information remains stable, but its readout efficiency in association cortices increases. We investigated this question by imaging neuronal activity in mouse primary somatosensory cortex before, during, and after learning of an object localization task. We quantified sensory- and behavior-related information and estimated how much sensory information was used to instruct perceptual choices as learning progressed. We find that sensory information increases from the start of training, while choice information is mostly present in the later stages of learning. Additionally, the readout of sensory information becomes more efficient with learning as early as in the primary sensory cortex. Together, our results highlight the importance of primary cortical neurons in perceptual learning.
Subject(s)
Learning , Neurons , Somatosensory Cortex , Animals , Somatosensory Cortex/physiology , Learning/physiology , Mice , Neurons/physiology , Male , Mice, Inbred C57BL , Behavior, Animal/physiology , FemaleABSTRACT
To investigate which activity patterns in sensory cortex are relevant for perceptual decision-making, we combined two-photon calcium imaging and targeted two-photon optogenetics to interrogate barrel cortex activity during perceptual discrimination. We trained mice to discriminate bilateral whisker deflections and report decisions by licking left or right. Two-photon calcium imaging revealed sparse coding of contralateral and ipsilateral whisker input in layer 2/3, with most neurons remaining silent during the task. Activating pyramidal neurons using two-photon holographic photostimulation evoked a perceptual bias that scaled with the number of neurons photostimulated. This effect was dominated by optogenetic activation of non-coding neurons, which did not show sensory or motor-related activity during task performance. Photostimulation also revealed potent recruitment of cortical inhibition during sensory processing, which strongly and preferentially suppressed non-coding neurons. Our results suggest that a pool of non-coding neurons, selectively suppressed by network inhibition during sensory processing, can be recruited to enhance perception.
Subject(s)
Neural Inhibition , Neurons , Optogenetics , Somatosensory Cortex , Vibrissae , Animals , Mice , Somatosensory Cortex/physiology , Vibrissae/physiology , Neural Inhibition/physiology , Neurons/physiology , Pyramidal Cells/physiology , Male , Photic Stimulation/methods , Mice, Inbred C57BLABSTRACT
BACKGROUND: Cysteine (Cys), glutathione (GSH), and homocysteine (Hcy), as three major biothiols are involved in a variety of physiological processes and play a crucial role in plant growth. Abnormal levels of Cys can cause plants to fail to grow properly. To date, although a very large number of fluorescent probes have been reported for the detection of biothiols, very few of them can be used for the selective discrimination of Cys from GSH and Hcy due to their structural similarity, and only a few of them can be used for plant imaging. RESULTS: Here, three fluorescent probes (o-/m-/p-TMA) based on TMN fluorophore and the ortho-/meta-/para-substituted maleimide recognition groups were constructed to investigate the selective response effect of Cys. Compared to the o-/m-TMA, p-TMA can selectively detect Cys over GSH and Hcy with a rapid response time (10 min) and a low detection limit (0.26 µM). The theoretical calculation confirmed that the intermediate p-TMA-Cys-int has shorter interatomic reaction distances (3.827 Å) compared to o-/m-TMA-Cys (5.533/5.287 Å), making it more suitable for further transcyclization reactions. Additionally, p-TMA has been employed for selective tracking of exogenous and endogenous Cys in Arabidopsis thaliana using both single-/two-photon fluorescence imaging. Furthermore, single cell walls produced obvious two-photon fluorescence signals, indicating that p-TMA can be used for high-concentration Cys analysis in single cells. Surprisingly, p-TMA can be used as a fluorescent dye for protein staining in SDS-PAGE with higher sensitivity (7.49 µg/mL) than classical Coomassie brilliant blue (14.11 µg/mL). SIGNIFICANCE: The outstanding properties of p-TMA make it a promising multifunctional molecular tool for the highly selective detection of Cys over GSH and Hcy in various complex environments, including water solutions, zebrafish, and plants. Additionally, it has the potential to be developed as a fluorescent dye for a simple and fast SDS-PAGE fluorescence staining method.
Subject(s)
Cysteine , Electrophoresis, Polyacrylamide Gel , Fluorescent Dyes , Glutathione , Homocysteine , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Cysteine/analysis , Cysteine/chemistry , Glutathione/analysis , Glutathione/chemistry , Homocysteine/analysis , Homocysteine/chemistry , Animals , Photons , Optical Imaging , Arabidopsis/chemistry , Humans , Cyclization , ZebrafishABSTRACT
Norepinephrine (NE), a neuromodulator released by locus ceruleus (LC) neurons throughout the cortex, influences arousal and learning through extrasynaptic vesicle exocytosis. While NE within cortical regions has been viewed as a homogenous field, recent studies have demonstrated heterogeneous axonal dynamics and advances in GPCR-based fluorescent sensors permit direct observation of the local dynamics of NE at cellular scale. To investigate how the spatiotemporal dynamics of NE release in the prefrontal cortex (PFC) affect neuronal firing, we employed in vivo two-photon imaging of layer 2/3 of the PFC in order to observe fine-scale neuronal calcium and NE dynamics concurrently. In this proof of principle study, we found that local and global NE fields can decouple from one another, providing a substrate for local NE spatiotemporal activity patterns. Optic flow analysis revealed putative release and reuptake events which can occur at the same location, albeit at different times, indicating the potential to create a heterogeneous NE field. Utilizing generalized linear models, we demonstrated that cellular Ca2+ fluctuations are influenced by both the local and global NE field. However, during periods of local/global NE field decoupling, the local field drives cell firing dynamics rather than the global field. These findings underscore the significance of localized, phasic NE fluctuations for structuring cell firing, which may provide local neuromodulatory control of cortical activity.
Subject(s)
Calcium , Neurons , Norepinephrine , Prefrontal Cortex , Animals , Prefrontal Cortex/physiology , Prefrontal Cortex/metabolism , Norepinephrine/metabolism , Neurons/physiology , Neurons/metabolism , Calcium/metabolism , Male , Action Potentials/physiology , Mice, Inbred C57BL , Mice , FemaleABSTRACT
Significance: The initiation of goal-directed actions is a complex process involving the medial prefrontal cortex and dopaminergic inputs through the mesocortical pathway. However, it is unclear what information the mesocortical pathway conveys and how it impacts action initiation. In this study, we unveiled the indispensable role of mesocortical axon terminals in encoding the execution of movements in self-initiated actions. Aim: To investigate the role of mesocortical axon terminals in encoding the execution of movements in self-initiated actions. Approach: We designed a lever-press task in which mice internally determine the timing of the press, receiving a larger reward for longer waiting periods. Results: Our study revealed that self-initiated actions depend on dopaminergic signaling mediated by D2 receptors, whereas sensory-triggered lever-press actions do not involve D2 signaling. Microprism-mediated two-photon calcium imaging further demonstrated ramping activity in mesocortical axon terminals approximately 0.5 s before the self-initiated lever press. Remarkably, the ramping patterns remained consistent whether the mice responded to cues immediately for a smaller reward or held their response for a larger reward. Conclusions: We conclude that mesocortical dopamine axon terminals encode the timing of self-initiated actions, shedding light on a crucial aspect of the intricate neural mechanisms governing goal-directed behavior.
ABSTRACT
Midbrain dopamine neurons impact neural processing in the prefrontal cortex (PFC) through mesocortical projections. However, the signals conveyed by dopamine projections to the PFC remain unclear, particularly at the single-axon level. Here, we investigated dopaminergic axonal activity in the medial PFC (mPFC) during reward and aversive processing. By optimizing microprism-mediated two-photon calcium imaging of dopamine axon terminals, we found diverse activity in dopamine axons responsive to both reward and aversive stimuli. Some axons exhibited a preference for reward, while others favored aversive stimuli, and there was a strong bias for the latter at the population level. Long-term longitudinal imaging revealed that the preference was maintained in reward- and aversive-preferring axons throughout classical conditioning in which rewarding and aversive stimuli were paired with preceding auditory cues. However, as mice learned to discriminate reward or aversive cues, a cue activity preference gradually developed only in aversive-preferring axons. We inferred the trial-by-trial cue discrimination based on machine learning using anticipatory licking or facial expressions, and found that successful discrimination was accompanied by sharper selectivity for the aversive cue in aversive-preferring axons. Our findings indicate that a group of mesocortical dopamine axons encodes aversive-related signals, which are modulated by both classical conditioning across days and trial-by-trial discrimination within a day.
Subject(s)
Axons , Conditioning, Classical , Dopaminergic Neurons , Prefrontal Cortex , Animals , Prefrontal Cortex/physiology , Mice , Axons/physiology , Conditioning, Classical/physiology , Dopaminergic Neurons/physiology , Male , Reward , Dopamine/metabolism , Mice, Inbred C57BL , CuesABSTRACT
Background: The treatment of patellar tendon injury has always been an unsolved problem, and mechanical characterization is very important for its repair and reconstruction. Elastin is a contributor to mechanics, but it is not clear how it affects the elasticity, viscoelastic properties, and structure of patellar tendon. Methods: The patellar tendons from six fresh adult experimental pigs were used in this study and they were made into 77 samples. The patellar tendon was specifically degraded by elastase, and the regional mechanical response and structural changes were investigated by: (1) Based on the previous study of elastase treatment conditions, the biochemical quantification of collagen, glycosaminoglycan and total protein was carried out; (2) The patellar tendon was divided into the proximal, central, and distal regions, and then the axial tensile test and stress relaxation test were performed before and after phosphate-buffered saline (PBS) or elastase treatment; (3) The dynamic constitutive model was established by the obtained mechanical data; (4) The structural relationship between elastin and collagen fibers was analyzed by two-photon microscopy and histology. Results: There was no statistical difference in mechanics between patellar tendon regions. Compared with those before elastase treatment, the low tensile modulus decreased by 75%-80%, the high tensile modulus decreased by 38%-47%, and the transition strain was prolonged after treatment. For viscoelastic behavior, the stress relaxation increased, the initial slope increased by 55%, the saturation slope increased by 44%, and the transition time increased by 25% after enzyme treatment. Elastin degradation made the collagen fibers of patellar tendon become disordered and looser, and the fiber wavelength increased significantly. Conclusion: The results of this study show that elastin plays an important role in the mechanical properties and fiber structure stability of patellar tendon, which supplements the structure-function relationship information of patellar tendon. The established constitutive model is of great significance to the prediction, repair and replacement of patellar tendon injury. In addition, human patellar tendon has a higher elastin content, so the results of this study can provide supporting information on the natural properties of tendon elastin degradation and guide the development of artificial patellar tendon biomaterials.
ABSTRACT
A promising therapeutic strategy in cancer treatment merges photodynamic therapy (PDT) induced apoptosis with ferroptosis, a form of programmed cell death governed by iron-dependent lipid peroxidation. Given the pivotal role of mitochondria in ferroptosis, the development of photosensitizers that specifically provoke mitochondrial dysfunction and consequentially trigger ferroptosis via PDT is of significant interest. To this end, we have designed and synthesized a novel nanoparticle, termed FECTPN, tailored to address this requisite. FECTPN harnesses a trifecta of critical attributes: precision mitochondria targeting, photoactivation capability, pH-responsive drug release, and synergistic apoptosis-ferroptosis antitumor treatment. This nanoparticle was formulated by conjugating an asymmetric silicon phthalocyanine, Chol-SiPc-TPP, with the ferroptosis inducer Erastin onto a ferritin. The Chol-SiPc-TPP is a chemically crafted entity featuring cholesteryl (Chol) and triphenylphosphine (TPP) functionalities bonded axially to the silicon phthalocyanine, enhancing mitochondrial affinity and leading to effective PDT and subsequent apoptosis of cells. Upon cellular uptake, FECTPN preferentially localizes to mitochondria, facilitated by Chol-SiPc-TPP's targeting mechanics. Photoactivation induces the synchronized release of Chol-SiPc-TPP and Erastin in the mitochondria's alkaline domain, driving the escalation of both ROSs and lipid peroxidation. These processes culminate in elevated antitumor activity compared to the singular application of Chol-SiPc-TPP-mediated PDT. A notable observation is the pronounced enhancement in glutathione peroxidase-4 (GPX4) expression within MCF-7 cells treated with FECTPN and subjected to light exposure, reflecting intensified oxidative stress. This study offers compelling evidence that FECTPN can effectively induce ferroptosis and reinforces the paradigm of a synergistic apoptosis-ferroptosis pathway in cancer therapy, proposing a novel route for augmented antitumor treatments.
Subject(s)
Antineoplastic Agents , Apoptosis , Ferroptosis , Indoles , Mitochondria , Nanoparticles , Organosilicon Compounds , Photochemotherapy , Photosensitizing Agents , Indoles/chemistry , Indoles/pharmacology , Apoptosis/drug effects , Humans , Mitochondria/metabolism , Mitochondria/drug effects , Ferroptosis/drug effects , Nanoparticles/chemistry , Organosilicon Compounds/chemistry , Organosilicon Compounds/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Particle Size , Cell Survival/drug effects , Surface PropertiesABSTRACT
Autism spectrum disorder (ASD) is often associated with social communication impairments and specific sound processing deficits, for example, problems in following speech in noisy environments. To investigate underlying neuronal processing defects located in the auditory cortex (AC), we performed two-photon Ca2+ imaging in FMR1 (fragile X messenger ribonucleoprotein 1) knock-out (KO) mice, a model for fragile X syndrome (FXS), the most common cause of hereditary ASD in humans. For primary AC (A1) and the anterior auditory field (AAF), topographic frequency representation was less ordered compared with control animals. We additionally analyzed ensemble AC activity in response to various sounds and found subfield-specific differences. In A1, ensemble correlations were lower in general, while in secondary AC (A2), correlations were higher in response to complex sounds, but not to pure tones. Furthermore, sound specificity of ensemble activity was decreased in AAF. Repeating these experiments 1â week later revealed no major differences regarding representational drift. Nevertheless, we found subfield- and genotype-specific changes in ensemble correlation values between the two times points, hinting at alterations in network stability in FMR1 KO mice. These detailed insights into AC network activity and topography in FMR1 KO mice add to the understanding of auditory processing defects in FXS.
Subject(s)
Auditory Cortex , Disease Models, Animal , Fragile X Mental Retardation Protein , Fragile X Syndrome , Mice, Knockout , Animals , Auditory Cortex/physiopathology , Fragile X Syndrome/physiopathology , Fragile X Syndrome/genetics , Fragile X Mental Retardation Protein/genetics , Male , Mice, Inbred C57BL , Acoustic Stimulation , Auditory Perception/physiology , Mice , Calcium/metabolismABSTRACT
The superior colliculus (SC) is a prominent and conserved visual center in all vertebrates. In mice, the most superficial lamina of the SC is enriched with neurons that are selective for the moving direction of visual stimuli. Here, we study how these direction selective neurons respond to complex motion patterns known as plaids, using two-photon calcium imaging in awake male and female mice. The plaid pattern consists of two superimposed sinusoidal gratings moving in different directions, giving an apparent pattern direction that lies between the directions of the two component gratings. Most direction selective neurons in the mouse SC respond robustly to the plaids and show a high selectivity for the moving direction of the plaid pattern but not of its components. Pattern motion selectivity is seen in both excitatory and inhibitory SC neurons and is especially prevalent in response to plaids with large cross angles between the two component gratings. However, retinal inputs to the SC are ambiguous in their selectivity to pattern versus component motion. Modeling suggests that pattern motion selectivity in the SC can arise from a nonlinear transformation of converging retinal inputs. In contrast, the prevalence of pattern motion selective neurons is not seen in the primary visual cortex (V1). These results demonstrate an interesting difference between the SC and V1 in motion processing and reveal the SC as an important site for encoding pattern motion.
Subject(s)
Mice, Inbred C57BL , Motion Perception , Photic Stimulation , Retina , Superior Colliculi , Visual Pathways , Animals , Superior Colliculi/physiology , Motion Perception/physiology , Mice , Male , Female , Retina/physiology , Photic Stimulation/methods , Visual Pathways/physiology , Neurons/physiology , Pattern Recognition, Visual/physiologyABSTRACT
Primates rely on two eyes to perceive depth, while maintaining stable vision when either one eye or both eyes are open. Although psychophysical and modeling studies have investigated how monocular signals are combined to form binocular vision, the underlying neuronal mechanisms, particularly in V1 where most neurons exhibit binocularity with varying eye preferences, remain poorly understood. Here, we used two-photon calcium imaging to compare the monocular and binocular responses of thousands of simultaneously recorded V1 superficial-layer neurons in three awake macaques. During monocular stimulation, neurons preferring the stimulated eye exhibited significantly stronger responses compared to those preferring both eyes. However, during binocular stimulation, the responses of neurons preferring either eye were suppressed on the average, while those preferring both eyes were enhanced, resulting in similar neuronal responses irrespective of their eye preferences, and an overall response level similar to that with monocular viewing. A neuronally realistic model of binocular combination, which incorporates ocular dominance-dependent divisive interocular inhibition and binocular summation, is proposed to account for these findings.