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A longstanding goal in neuroscience has been to image membrane voltage across a population of individual neurons in an awake, behaving mammal. Here we describe a genetically encoded fluorescent voltage indicator, SomArchon, which exhibits millisecond response times and is compatible with optogenetic control, and which increases the sensitivity, signal-to-noise ratio, and number of neurons observable several-fold over previously published fully genetically encoded reagents1-8. Under conventional one-photon microscopy, SomArchon enables the routine population analysis of around 13 neurons at once, in multiple brain regions (cortex, hippocampus, and striatum) of head-fixed, awake, behaving mice. Using SomArchon, we detected both positive and negative responses of striatal neurons during movement, as previously reported by electrophysiology but not easily detected using modern calcium imaging techniques9-11, highlighting the power of voltage imaging to reveal bidirectional modulation. We also examined how spikes relate to the subthreshold theta oscillations of individual hippocampal neurons, with SomArchon showing that the spikes of individual neurons are more phase-locked to their own subthreshold theta oscillations than to local field potential theta oscillations. Thus, SomArchon reports both spikes and subthreshold voltage dynamics in awake, behaving mice.
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Biomarcadores Ambientales , Hipocampo/citología , Neuronas/fisiología , Imagen Óptica/métodos , Vigilia/fisiología , Potenciales de Acción/fisiología , Animales , Biomarcadores Ambientales/genética , Hipocampo/diagnóstico por imagen , Ratones , OptogenéticaRESUMEN
Cortical circuits encoding sensory information consist of populations of neurons, yet how information aggregates via pooling individual cells remains poorly understood. Such pooling may be particularly important in noisy settings where single-neuron encoding is degraded. One example is the cocktail party problem, with competing sounds from multiple spatial locations. How populations of neurons in auditory cortex code competing sounds have not been previously investigated. Here, we apply a novel information-theoretic approach to estimate information in populations of neurons in mouse auditory cortex about competing sounds from multiple spatial locations, including both summed population (SP) and labeled line (LL) codes. We find that a small subset of neurons is sufficient to nearly maximize mutual information over different spatial configurations, with the labeled line code outperforming the summed population code and approaching information levels attained in the absence of competing stimuli. Finally, information in the labeled line code increases with spatial separation between target and masker, in correspondence with behavioral results on spatial release from masking in humans and animals. Taken together, our results reveal that a compact population of neurons in auditory cortex provides a robust code for competing sounds from different spatial locations.NEW & NOTEWORTHY Little is known about how populations of neurons within cortical circuits encode sensory stimuli in the presence of competing stimuli at other spatial locations. Here, we investigate this problem in auditory cortex using a recently proposed information-theoretic approach. We find a small subset of neurons nearly maximizes information about target sounds in the presence of competing maskers, approaching information levels for isolated stimuli, and provides a noise-robust code for sounds in a complex auditory scene.
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Corteza Auditiva , Humanos , Animales , Ratones , Sonido , NeuronasRESUMEN
Theta and gamma rhythms and their cross-frequency coupling play critical roles in perception, attention, learning, and memory. Available data suggest that forebrain acetylcholine (ACh) signaling promotes theta-gamma coupling, although the mechanism has not been identified. Recent evidence suggests that cholinergic signaling is both temporally and spatially constrained, in contrast to the traditional notion of slow, spatially homogeneous, and diffuse neuromodulation. Here, we find that spatially constrained cholinergic stimulation can generate theta-modulated gamma rhythms. Using biophysically-based excitatory-inhibitory (E-I) neural network models, we simulate the effects of ACh on neural excitability by varying the conductance of a muscarinic receptor-regulated K+ current. In E-I networks with local excitatory connectivity and global inhibitory connectivity, we demonstrate that theta-gamma-coupled firing patterns emerge in ACh modulated network regions. Stable gamma-modulated firing arises within regions with high ACh signaling, while theta or mixed theta-gamma activity occurs at the peripheries of these regions. High gamma activity also alternates between different high-ACh regions, at theta frequency. Our results are the first to indicate a causal role for spatially heterogenous ACh signaling in the emergence of localized theta-gamma rhythmicity. Our findings also provide novel insights into mechanisms by which ACh signaling supports the brain region-specific attentional processing of sensory information.
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Neuronas Colinérgicas/fisiología , Ritmo Gamma/fisiología , Modelos Neurológicos , Ritmo Teta/fisiología , Acetilcolina/farmacología , Acetilcolina/fisiología , Animales , Colinérgicos/farmacología , Neuronas Colinérgicas/efectos de los fármacos , Biología Computacional , Simulación por Computador , Ritmo Gamma/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Redes Neurales de la Computación , Prosencéfalo/efectos de los fármacos , Prosencéfalo/fisiología , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/fisiología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Ritmo Teta/efectos de los fármacosRESUMEN
The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses.
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Acetilcolina/metabolismo , Conducta Animal/fisiología , Neuronas Colinérgicas/metabolismo , Corteza Prefrontal/metabolismo , Transmisión Sináptica/fisiología , Animales , Neuronas Colinérgicas/citología , Halorrodopsinas/biosíntesis , Halorrodopsinas/genética , Ratones , Ratones Transgénicos , Corteza Prefrontal/citologíaRESUMEN
The capacity for using external cues to guide behavior ("cue detection") constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta-gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection.SIGNIFICANCE STATEMENT The capacity of learned cues to direct attention and guide responding ("cue detection") is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex contribute to this process; however, the relationship between these neuronal mechanisms is not well understood. Using a combination of in vivo neurochemistry, neurophysiology, and pharmacological methods, we demonstrate that cue-evoked acetylcholine release, through distinct actions at both nicotinic and muscarinic receptors, triggers a procession of neural oscillations that map onto the multiple stages of cue detection. Our data offer new insights into cholinergic function by revealing the temporally orchestrated changes in prefrontal network synchrony modulated by acetylcholine release during cue detection.
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Acetilcolina/metabolismo , Neuronas Colinérgicas/fisiología , Señales (Psicología) , Ritmo Gamma/fisiología , Corteza Prefrontal/fisiología , Ritmo Teta/fisiología , Animales , Conducta Animal/fisiología , Relojes Biológicos/fisiología , Masculino , Neurotransmisores/metabolismo , Ratas , Recompensa , Transmisión Sináptica/fisiología , Percepción Visual/fisiologíaRESUMEN
In addition to the neuromodulatory role of cholinergic systems, brief, temporally discrete cholinergic release events, or "transients", have been associated with the detection of cues in attention tasks. Here we review four main findings about cholinergic transients during cognitive processing. Cholinergic transients are: (1) associated with the detection of a cue and influenced by cognitive state; (2) not dependent on reward outcome, although the timing of the transient peak co-varies with the temporal relationship between detection and reward delivery; (3) correlated with the mobilization of the cue-evoked response; (4) causal mediators of shifts from monitoring to cue detection. We next discuss some of the key questions concerning the timing and occurrence of transients within the framework of available evidence including: (1) Why does the shift from monitoring to cue detection require a transient? (2) What determines whether a cholinergic transient will be generated? (3) How can cognitive state influence transient occurrence? (4) Why do cholinergic transients peak at around the time of reward delivery? (5) Is there evidence of cholinergic transients in humans? We conclude by outlining future research studies necessary to more fully understand the role of cholinergic transients in mediating cue detection.
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Acetilcolina/metabolismo , Encéfalo/metabolismo , Neuronas Colinérgicas/metabolismo , Animales , Atención/fisiología , Cognición/fisiología , Señales (Psicología) , Humanos , RecompensaRESUMEN
Traditional descriptions of the basal forebrain cholinergic projection system to the cortex have focused on neuromodulatory influences, that is, mechanisms that modulate cortical information processing but are not necessary for mediating discrete behavioral responses and cognitive operations. This review summarises and conceptualises the evidence in support of more deterministic contributions of cholinergic projections to cortical information processing. Through presynaptic receptors expressed on cholinergic terminals, thalamocortical and corticocortical projections can evoke brief cholinergic release events. These acetylcholine (ACh) release events occur on a fast, sub-second to seconds-long time scale ('transients'). In rats performing a task requiring the detection of cues as well as the report of non-cue events cholinergic transients mediate the detection of cues specifically in trials that involve a shift from a state of monitoring for cues to cue-directed responding. Accordingly, ill-timed cholinergic transients, generated using optogenetic methods, force false detections in trials without cues. We propose that the evidence is consistent with the hypothesis that cholinergic transients reduce detection uncertainty in such trials. Furthermore, the evidence on the functions of the neuromodulatory component of cholinergic neurotransmission suggests that higher levels of neuromodulation favor staying-on-task over alternative action. In other terms, higher cholinergic neuromodulation reduces opportunity costs. Evidence indicating a similar integration of other ascending projection systems, including noradrenergic and serotonergic systems, into cortical circuitry remains sparse, largely because of the limited information about local presynaptic regulation and the limitations of current techniques in measuring fast and transient neurotransmitter release events in these systems.
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Acetilcolina/metabolismo , Corteza Cerebral/fisiología , Potenciales Sinápticos , Animales , Corteza Cerebral/metabolismo , Humanos , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología , Tálamo/metabolismo , Tálamo/fisiologíaRESUMEN
Stepping movement is delta (1-4 Hz) rhythmic and depends on sensory inputs. In addition to delta rhythms, beta (10-30 Hz) frequency dynamics are also prominent in the motor circuits and are coupled to neuronal delta rhythms both at the network and the cellular levels. Since beta rhythms are broadly supported by cortical and subcortical sensorimotor circuits, we explore how beta-frequency sensory stimulation influences delta-rhythmic stepping movement, and dorsal striatal circuit regulation of stepping. We delivered audiovisual stimulation at 10 Hz or 145 Hz to mice voluntarily locomoting, while simultaneously recording stepping movement, striatal cellular calcium dynamics and local field potentials (LFPs). We found that 10 Hz, but not 145 Hz stimulation prominently entrained striatal LFPs. Even though sensory stimulation at both frequencies promoted locomotion and desynchronized striatal network, only 10 Hz stimulation enhanced the delta rhythmicity of stepping movement and strengthened the coupling between stepping and striatal LFP delta and beta oscillations. These results demonstrate that higher frequency sensory stimulation can modulate lower frequency dorsal striatal neural dynamics and improve stepping rhythmicity, highlighting the translational potential of non-invasive beta-frequency sensory stimulation for improving gait.
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Motivated by the unexplored potential of in vitro neural systems for computing and by the corresponding need of versatile, scalable interfaces for multimodal interaction, an accurate, modular, fully customizable, and portable recording/stimulation solution that can be easily fabricated, robustly operated, and broadly disseminated is presented. This approach entails a reconfigurable platform that works across multiple industry standards and that enables a complete signal chain, from neural substrates sampled through micro-electrode arrays (MEAs) to data acquisition, downstream analysis, and cloud storage. Built-in modularity supports the seamless integration of electrical/optical stimulation and fluidic interfaces. Custom MEA fabrication leverages maskless photolithography, favoring the rapid prototyping of a variety of configurations, spatial topologies, and constitutive materials. Through a dedicated analysis and management software suite, the utility and robustness of this system are demonstrated across neural cultures and applications, including embryonic stem cell-derived and primary neurons, organotypic brain slices, 3D engineered tissue mimics, concurrent calcium imaging, and long-term recording. Overall, this technology, termed "mind in vitro" to underscore the computing inspiration, provides an end-to-end solution that can be widely deployed due to its affordable (>10× cost reduction) and open-source nature, catering to the expanding needs of both conventional and unconventional electrophysiology.
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Encéfalo , Neuronas , Electrodos , Encéfalo/fisiología , Neuronas/fisiología , Estimulación Eléctrica , Fenómenos Electrofisiológicos/fisiologíaRESUMEN
Rapid eye movement (REM) sleep enhances hippocampus-dependent associative memory, but REM deprivation has little impact on striatum-dependent procedural learning. Antidepressant medications are known to inhibit REM sleep, but it is not well understood if antidepressant treatments impact learning and memory. We explored antidepressant REM suppression effects on learning by training animals daily on a spatial task under familiar and novel conditions, followed by training on a procedural memory task. Daily treatment with the antidepressant and norepinephrine reuptake inhibitor desipramine (DMI) strongly suppressed REM sleep in rats for several hours, as has been described in humans. We also found that DMI treatment reduced the spindle-rich transition-to-REM sleep state (TR), which has not been previously reported. DMI REM suppression gradually weakened performance on a once familiar hippocampus-dependent maze (reconsolidation error). DMI also impaired learning of the novel maze (consolidation error). Unexpectedly, learning of novel reward positions and memory of familiar positions were equally and oppositely correlated with amounts of TR sleep. Conversely, DMI treatment enhanced performance on a separate striatum-dependent, procedural T-maze task that was positively correlated with the amounts of slow-wave sleep (SWS). Our results suggest that learning strategy switches in patients taking REM sleep-suppressing antidepressants might serve to offset sleep-dependent hippocampal impairments to partially preserve performance. State-performance correlations support a model wherein reconsolidation of hippocampus-dependent familiar memories occurs during REM sleep, novel information is incorporated and consolidated during TR, and dorsal striatum-dependent procedural learning is augmented during SWS.
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Antidepresivos Tricíclicos/farmacología , Condicionamiento Operante/efectos de los fármacos , Cuerpo Estriado/fisiología , Desipramina/farmacología , Hipocampo/efectos de los fármacos , Fases del Sueño/efectos de los fármacos , Análisis de Varianza , Animales , Cuerpo Estriado/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Electrodos Implantados , Electroencefalografía , Electromiografía , Conducta Exploratoria/efectos de los fármacos , Alimentos , Hipocampo/fisiología , Discapacidades para el Aprendizaje/inducido químicamente , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Motivación/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Fases del Sueño/fisiología , Percepción Espacial/efectos de los fármacosRESUMEN
Circadian rhythms influence a variety of physiological and behavioral processes; however, little is known about how circadian rhythms interact with the organisms' ability to acquire and retain information about their environment. These experiments tested whether rats trained outside their endogenous active period demonstrate the same rate of acquisition, daily performance, and remote memory ability as their nocturnally trained counterparts in tasks of sustained attention and spatial memory. Furthermore, we explored how daily task training influenced circadian patterns of activity. We found that rats demonstrate better acquisition and performance on an operant task requiring attentional effort when trained during the dark-phase. Time of day did not affect acquisition or performance on the Morris water maze; however, when animals were retested 2 wk after their last day of training, they showed better remote memory if training originally occurred during the dark-phase. Finally, attentional, but not spatial, task performance during the light-phase promotes a shift toward diurnality and the synchronization of activity to the time of daily training; this shift was most robust when the demands on the cognitive control of attention were highest. Our findings support a theory of bidirectional interactions between cognitive performance and circadian processes and are consistent with the view that the circadian abnormalities associated with shift-work, aging, and neuropsychiatric illnesses may contribute to the deleterious effects on cognition often present in these populations. Furthermore, these findings suggest that time of day should be an important consideration for a variety of cognitive tasks principally used in psychological and neuroscience research.
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Atención/fisiología , Conducta Animal/fisiología , Ritmo Circadiano/fisiología , Cognición/fisiología , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Percepción Espacial/fisiología , Factores de TiempoRESUMEN
Rhythmic neural network activity has been broadly linked to behavior. However, it is unclear how membrane potentials of individual neurons track behavioral rhythms, even though many neurons exhibit pace-making properties in isolated brain circuits. To examine whether single-cell voltage rhythmicity is coupled to behavioral rhythms, we focused on delta-frequencies (1-4 Hz) that are known to occur at both the neural network and behavioral levels. We performed membrane voltage imaging of individual striatal neurons simultaneously with network-level local field potential recordings in mice during voluntary movement. We report sustained delta oscillations in the membrane potentials of many striatal neurons, particularly cholinergic interneurons, which organize spikes and network oscillations at beta-frequencies (20-40 Hz) associated with locomotion. Furthermore, the delta-frequency patterned cellular dynamics are coupled to animals' stepping cycles. Thus, delta-rhythmic cellular dynamics in cholinergic interneurons, known for their autonomous pace-making capabilities, play an important role in regulating network rhythmicity and movement patterning.
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Cuerpo Estriado , Interneuronas , Animales , Ratones , Interneuronas/fisiología , Cuerpo Estriado/fisiología , Neuronas/fisiología , Potenciales de la Membrana , ColinérgicosRESUMEN
Cortical representations supporting many cognitive abilities emerge from underlying circuits comprised of several different cell types. However, cell type-specific contributions to rate and timing-based cortical coding are not well-understood. Here, we investigated the role of parvalbumin neurons in cortical complex scene analysis. Many complex scenes contain sensory stimuli which are highly dynamic in time and compete with stimuli at other spatial locations. Parvalbumin neurons play a fundamental role in balancing excitation and inhibition in cortex and sculpting cortical temporal dynamics; yet their specific role in encoding complex scenes via timing-based coding, and the robustness of temporal representations to spatial competition, has not been investigated. Here, we address these questions in auditory cortex of mice using a cocktail party-like paradigm, integrating electrophysiology, optogenetic manipulations, and a family of spike-distance metrics, to dissect parvalbumin neurons' contributions towards rate and timing-based coding. We find that suppressing parvalbumin neurons degrades cortical discrimination of dynamic sounds in a cocktail party-like setting via changes in rapid temporal modulations in rate and spike timing, and over a wide range of time-scales. Our findings suggest that parvalbumin neurons play a critical role in enhancing cortical temporal coding and reducing cortical noise, thereby improving representations of dynamic stimuli in complex scenes.
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Corteza Auditiva , Percepción Auditiva , Neuronas , Parvalbúminas , Animales , Ratones , Neuronas/fisiología , Corteza Auditiva/fisiología , OptogenéticaRESUMEN
Hippocampal CA1 neurons generate single spikes and stereotyped bursts of spikes. However, it is unclear how individual neurons dynamically switch between these output modes and whether these two spiking outputs relay distinct information. We performed extracellular recordings in spatially navigating rats and cellular voltage imaging and optogenetics in awake mice. We found that spike bursts are preferentially linked to cellular and network theta rhythms (3-12 Hz) and encode an animal's position via theta phase precession, particularly as animals are entering a place field. In contrast, single spikes exhibit additional coupling to gamma rhythms (30-100 Hz), particularly as animals leave a place field. Biophysical modeling suggests that intracellular properties alone are sufficient to explain the observed input frequency-dependent spike coding. Thus, hippocampal neurons regulate the generation of bursts and single spikes according to frequency-specific network and intracellular dynamics, suggesting that these spiking modes perform distinct computations to support spatial behavior.
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Ritmo Gamma , Navegación Espacial , Ratas , Ratones , Animales , Potenciales de Acción/fisiología , Hipocampo/fisiología , Neuronas/fisiología , Ritmo Teta/fisiologíaRESUMEN
Listening in noisy or complex sound environments is difficult for individuals with normal hearing and can be a debilitating impairment for those with hearing loss. Extracting meaningful information from a complex acoustic environment requires the ability to accurately encode specific sound features under highly variable listening conditions and segregate distinct sound streams from multiple overlapping sources. The auditory system employs a variety of mechanisms to achieve this auditory scene analysis. First, neurons across levels of the auditory system exhibit compensatory adaptations to their gain and dynamic range in response to prevailing sound stimulus statistics in the environment. These adaptations allow for robust representations of sound features that are to a large degree invariant to the level of background noise. Second, listeners can selectively attend to a desired sound target in an environment with multiple sound sources. This selective auditory attention is another form of sensory gain control, enhancing the representation of an attended sound source while suppressing responses to unattended sounds. This review will examine both "bottom-up" gain alterations in response to changes in environmental sound statistics as well as "top-down" mechanisms that allow for selective extraction of specific sound features in a complex auditory scene. Finally, we will discuss how hearing loss interacts with these gain control mechanisms, and the adaptive and/or maladaptive perceptual consequences of this plasticity.
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Dopamine degeneration in Parkinson's disease (PD) dysregulates the striatal neural network and causes motor deficits. However, it is unclear how altered striatal circuits relate to dopamine-acetylcholine chemical imbalance and abnormal local field potential (LFP) oscillations observed in PD. We perform a multimodal analysis of the dorsal striatum using cell-type-specific calcium imaging and LFP recording. We reveal that dopamine depletion selectively enhances LFP beta oscillations during impaired locomotion, supporting beta oscillations as a biomarker for PD. We further demonstrate that dynamic cholinergic interneuron activity during locomotion remains unaltered, even though cholinergic tone is implicated in PD. Instead, dysfunctional striatal output arises from elevated coordination within striatal output neurons, which is accompanied by reduced locomotor encoding of parvalbumin interneurons and transient pathological LFP high-gamma oscillations. These results identify a pathological striatal circuit state following dopamine depletion where distinct striatal neuron subtypes are selectively coordinated with LFP oscillations during locomotion.
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Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Neuronas/metabolismo , Trastornos Parkinsonianos/fisiopatología , Animales , Cuerpo Estriado/metabolismo , Femenino , Locomoción/fisiología , Masculino , Ratones , Neuronas/patología , Trastornos Parkinsonianos/metabolismoRESUMEN
Trace conditioning and extinction learning depend on the hippocampus, but it remains unclear how neural activity in the hippocampus is modulated during these two different behavioral processes. To explore this question, we performed calcium imaging from a large number of individual CA1 neurons during both trace eye-blink conditioning and subsequent extinction learning in mice. Our findings reveal that distinct populations of CA1 cells contribute to trace conditioned learning versus extinction learning, as learning emerges. Furthermore, we examined network connectivity by calculating co-activity between CA1 neuron pairs and found that CA1 network connectivity patterns also differ between conditioning and extinction, even though the overall connectivity density remains constant. Together, our results demonstrate that distinct populations of hippocampal CA1 neurons, forming different sub-networks with unique connectivity patterns, encode different aspects of learning.
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Condicionamiento Clásico/fisiología , Condicionamiento Palpebral/fisiología , Extinción Psicológica , Neuronas/fisiología , Animales , Parpadeo/fisiología , Femenino , Ratones , Ratones Endogámicos C57BLRESUMEN
The inherent constraints on resolution, speed and field of view have hindered the development of high-speed, three-dimensional microscopy techniques over large scales. Here, we present a multiplane line-scan imaging strategy, which uses a series of axially distributed reflecting slits to probe different depths within a sample volume. Our technique enables the simultaneous imaging of an optically sectioned image stack with a single camera at frame rates of hundreds of hertz, without the need for axial scanning. We demonstrate the applicability of our system to monitor fast dynamics in biological samples by performing calcium imaging of neuronal activity in mouse brains and voltage imaging of cardiomyocytes in cardiac samples.
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Ultrasound modulates brain activity. However, it remains unclear how ultrasound affects individual neurons in the brain, where neural circuit architecture is intact and different brain regions exhibit distinct tissue properties. Using a high-resolution calcium imaging technique, we characterized the effect of ultrasound stimulation on thousands of individual neurons in the hippocampus and the motor cortex of awake mice. We found that brief 100-ms-long ultrasound pulses increase intracellular calcium in a large fraction of individual neurons in both brain regions. Ultrasound-evoked calcium response in hippocampal neurons exhibits a rapid onset with a latency shorter than 50 ms. The evoked response in the hippocampus is shorter in duration and smaller in magnitude than that in the motor cortex. These results demonstrate that noninvasive ultrasound stimulation transiently increases intracellular calcium in individual neurons in awake mice, and the evoked response profiles are brain region specific.