Biology subjects

Cardin, J. A.

Publications and source records attributed to Cardin, J. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Spatiotemporally dynamic noradrenergic regulation of cortical networks

Brain activity and cognition exhibit state-dependent fluctuations that may reflect the influence of neuromodulatory systems, including norepinephrine (NE). Although the activity of noradrenergic neurons is strongly coupled to sleep-wake cycles and pupil dynamics, suggesting a global arousal signal, recent evidence suggests potentially modular partitioning of these cells. In addition, it is unclear whether different neuromodulatory signals exhibit distinct spatiotemporal patterns. We performed simultaneous, dual color mesoscopic imaging of either NE and calcium or NE and acetylcholine (ACh) signals across the neocortex, along with high-density electrophysiology, to investigate the relationship between NE release and neural activity. We find that the pattern of cortical NE signaling varies with behavioral state and is associated with enhanced functional connectivity. Simultaneous imaging of NE and ACh reveals spatiotemporally dynamic coupling between signals. Finally, NE signaling and functional connectivity are disrupted by sleep deprivation. Overall, our findings demonstrate that NE provides a multimodal signal that links transitions in behavioral state to cortical network interactions.

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bioRxiv2026

Visual experience drives functional reorganization of cortical GABAergic circuits

Sensory experience shapes the development and function of neocortical circuits. Although repeated exposure to sensory stimuli can alter cortical responses, the precise relationship between sensory experience and circuit interactions remains unclear. Here, we examine how cortical circuits are shaped by repeated exposure to varied visual stimuli. We find that visually evoked beta activity, a prominent pattern of visually evoked activity that relies on somatostatin-expressing (SST) GABAergic interneurons, is robustly potentiated by visual experience. Enhanced visual experience leads to increased responses in SST interneurons and suppressed responses in vasoactive intestinal peptide-expressing (VIP) interneurons. In association with this rebalancing of cortical inhibitory activity, experience increases the recruitment and visual selectivity of excitatory neurons. This enhancement is associated with increased SST-IN influence on nearby pyramidal neurons and requires SST-IN activity during visual experience. Visual experience thus selectively reorganizes adult dendrite-targeting inhibitory circuits, promoting network synchrony and enhancing sensory encoding by excitatory neurons.

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bioRxiv2025

Learning-dependent cholinergic plasticity reconfigures cortical circuit dynamics.

Neuromodulation by acetylcholine (ACh) plays a critical role in shaping neural dynamics in the neocortex as a function of development, behavioral state, and learning 1-6. Prior work suggests cholinergic signaling can act as a gate for the subsequent induction of circuit plasticity 3,7,8. However, modification of ACh release could also be a direct mechanism for the expression of cortical plasticity. Here, we combine widefield and 2-photon imaging in head-fixed mice to show that visual fear conditioning leads to a selective, cue-dependent release of ACh in primary visual cortex that enhances visually-evoked neuronal responses via excitation of layer 1 GABAergic interneurons and resulting disinhibition of local excitatory pyramidal neurons. Cholinergic signaling through muscarinic receptors in visual cortex is necessary for both learning and expression of conditioned fear behavior and enhanced visual representation. Our results demonstrate a novel capacity for conditioned release of ACh in sensory cortex to serve as a mechanism for sensory-guided behavioral learning. Rather than acting as a simple gate, cortical neuromodulation may thus play a central role in the expression of learned behavior.

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bioRxiv2025

Lateral septal inhibition of nucleus basalis through direct and indirect pathways in focal limbic seizures

Temporal lobe epilepsy (TLE) is the most common form of epilepsy and is characterized by focal seizures originating from limbic structures, including the hippocampus. Patients with TLE often experience impaired consciousness. A recent awake mouse model study demonstrated decreased cortical cholinergic innervation during focal seizures with impaired consciousness, based on cortical slow wave activity and decreased behavioral responsiveness. But the underlying mechanisms for reduced cortical cholinergic activity are not fully understood. This study employs the same awake mouse model combined with electrophysiology recordings in key network nodes, cell-specific calcium imaging in the lateral septum, and neurotransmitter sensing in one of the major subcortical cholinergic systems, the nucleus basalis of Meynert (NBM). We demonstrate that decreased cortical cholinergic innervation during focal seizures comes from both direct inhibition and indirect de-excitation of the NBM, showing a parallel pathway NBM suppression mechanism from the LS directly and through the paratenial thalamic nucleus indirectly. This work contributes to a deeper understanding of the neural processes involved in impaired consciousness during focal seizures and may open the way to new treatments for this disorder.

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bioRxiv2025

Selective changes in cortical cholinergic signaling during learning

Cognition relies on the function of local and long-range neural circuits in the neocortex, which are dynamically regulated by neuromodulatory signals including acetylcholine (ACh). Recent work suggests that the role of acetylcholine varies across cortical areas and behavioral states. In addition, the precise role of cholinergic signaling during learning and plasticity remains unclear. We performed simultaneous, dual-color mesoscopic imaging of ACh and calcium signaling in the neocortex of awake mice across multiple stages of visual task learning to identify learning-related plasticity in neural activity and cholinergic signaling. Using a novel Pattern Reconstruction and Interpretation with a Structured Multimodal transformer (PRISMT) model combining masked autoencoding with multimodal causal attention, we identified key cortical regions that reorganize with learning. We found that cholinergic signaling exhibited spatiotemporally selective plasticity in frontal cortical subnetworks during visual perceptual learning. Overall, our findings demonstrate the utility of transformer models for generating biologically interpretable insight into large multimodal datasets and link long-term functional reorganization of cortical networks to enhanced task performance.

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bioRxiv2024

Developmental trajectory of cortical somatostatin interneuron function

GABAergic inhibition is critical to the proper development of neocortical circuits. However, GABAergic interneurons are highly diverse and the developmental roles of distinct inhibitory subpopulations remain largely unclear. Dendrite-targeting, somatostatin-expressing interneurons (SST-INs) in the mature cortex regulate synaptic integration and plasticity in excitatory pyramidal neurons (PNs) and exhibit unique feature selectivity. Relatively little is known about early postnatal SST-IN activity or impact on surrounding local circuits. We examined juvenile SST-INs and PNs in mouse primary visual cortex. PNs exhibited stable visual responses and feature selectivity from eye opening onwards. In contrast, SST-INs developed visual responses and feature selectivity during the third postnatal week in parallel with a rapid increase in excitatory synaptic innervation. SST-INs largely exerted a multiplicative effect on nearby PN visual responses at all ages, but this impact increased over time. Our results identify a developmental window for the emergence of an inhibitory circuit mechanism for normalization.

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bioRxiv2023

Transthalamic input to higher-order cortex selectively conveys state information

Communication among different neocortical areas is largely thought to be mediated by long-range synaptic interactions between cortical neurons, with the thalamus providing only an initial relay of information from the sensory periphery. Higher-order thalamic nuclei receive strong synaptic inputs from the cortex and send robust projections back to other cortical areas, providing a distinct and potentially critical route for cortico-cortical communication. However, the relative contributions of corticocortical and thalamocortical inputs to higher-order cortical function remain unclear. Using imaging of cortical neurons and projection axon terminals in combination with optogenetic manipulations, we find that the higher-order visual thalamus of mice conveys a specialized stream of information to higher-order visual cortex. Whereas corticocortical projections from lower cortical areas convey robust visual information, higher-order thalamocortical projections convey strong behavioral state information. Together, these findings suggest a key role for higher-order thalamus in providing contextual signals that flexibly modulate sensory processing in higher-order cortex.

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bioRxiv2023

Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. We examined widespread alterations in functional connectivity following TBI using simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured using the controlled cortical impact (CCI) model of TBI. Combining CCI with widefield cortical imaging provides us with unprecedented access to characterize network connectivity changes throughout the entire injured cortex over time. Our data demonstrate that CCI profoundly disrupts functional connectivity immediately after injury, followed by partial recovery over 3 weeks. Examining discrete periods of locomotion and stillness reveals that CCI alters functional connectivity and reduces theta power only during periods of behavioral stillness. Together, these findings demonstrate that TBI causes dynamic, behavioral state-dependent changes in functional connectivity and ECoG activity across the cortex.

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bioRxiv2023

Beyond rhythm - A framework for understanding the frequency spectrum of neural activity

Cognitive and behavioral processes are often accompanied by changes within well-defined frequency bands of the local field potential (LFP i.e., the voltage induced by neuronal activity). These changes are detectable in the frequency domain using the Fourier transform and are often interpreted as neuronal oscillations. However, aside some well-known exceptions, the processes underlying such changes are difficult to track in time, making their oscillatory nature hard to verify. In addition, many non-periodic neural processes can also have spectra that emphasize specific frequencies. Thus, the notion that spectral changes reflect oscillations is likely too restrictive. In this study, we propose a simple yet versatile framework to understand the frequency spectra of neural recordings. Using simulations, we derive the Fourier spectra of periodic, quasi-periodic and non-periodic neural processes having diverse waveforms, illustrating how these attributes shape their spectral signatures. We then show how neural processes sum their energy in the local field potential in simulated and real-world recording scenarios. We find that the spectral power of neural processes is essentially determined by two aspects: 1) the distribution of neural events in time and 2) the waveform of the voltage induced by single neural events. Taken together, this work guides the interpretation of the Fourier spectrum of neural recordings and indicates that power increases in specific frequency bands do not necessarily reflect periodic neural activity.

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bioRxiv2023

VIP interneurons regulate cortical size tuning and visual perception

Local cortical circuit function is regulated by diverse populations of GABAergic interneurons with distinct properties and extensive interconnectivity. Inhibitory-to-inhibitory interactions between interneuron populations may play key roles in shaping circuit operation according to behavioral context. A specialized population of GABAergic interneurons that co-express vasoactive intestinal peptide (VIP-INs) are activated during arousal and locomotion and innervate other local interneurons and pyramidal neurons. Although modulation of VIP-IN activity by behavioral state has been extensively studied, their role in regulating information processing and selectivity is less well understood. Using a combination of cellular imaging, short and long-term manipulation, and perceptual behavior, we examined the impact of VIP-INs on their synaptic target populations in the primary visual cortex of awake behaving mice. We find that loss of VIP-IN activity alters the behavioral state-dependent modulation of somatostatin-expressing interneurons (SST-INs) but not pyramidal neurons (PNs). In contrast, reduced VIP-IN activity disrupts visual feature selectivity for stimulus size in both populations. Inhibitory-to inhibitory interactions thus directly shape the selectivity of GABAergic interneurons for sensory stimuli. Moreover, the impact of VIP-IN activity on perceptual behavior varies with visual context and is more acute for small than large visual cues. VIP-INs thus contribute to both state-dependent modulation of cortical circuit activity and sensory context-dependent perceptual performance.

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bioRxiv2022

The Cousa objective: a long working distance air objective for multiphoton imaging in vivo

Multiphoton microscopy can resolve fluorescent structures and dynamics deep in scattering tissue, but applying this technique in vivo can be limited by short working distance water-immersion objectives. Here we present an ultra long working distance (20 mm) air objective called the Cousa objective. It is optimized for performance across multiphoton imaging wavelengths, offers a > 4 mm2 field-of-view with submicron lateral resolution, and is compatible with commonly used multiphoton imaging systems. We share the full optical prescription, and report performance including in vivo 2-photon and 3-photon imaging in a range of species and preparations.

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bioRxiv2022

Flexible perceptual encoding by discrete gamma events

Spatiotemporal patterns of activity in the neocortex are linked to cognitive processes underlying behavior. However, identifying discrete underlying events within highly dynamic cortical network fluctuations remains a critical challenge. Here, we demonstrate a novel analytical method to track network events underlying state-dependent {beta}- (15-30Hz) and {gamma}- (30-80Hz) range activity in mouse primary visual cortex (V1). We find that {gamma} events are selectively associated with enhanced visual encoding by V1 neurons and {gamma} event rate increases prior to visually-cued behavior, accurately predicting single trial visual detection. This relationship between {gamma} events and behavior is sensory modality-specific and rapidly modulated by changes in task objectives. These findings illuminate a distinct role for transient patterns of cortical activity, indicating that {gamma} supports flexible encoding according to behavioral context.

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bioRxiv2021

Dual polarity voltage imaging reveals subthreshold dynamics and concurrent spiking patterns of multiple neuron-types

Genetically encoded fluorescent voltage indicators are ideally suited to reveal the millisecond-scale interactions among and between distinct, targeted cell populations. However, current indicator families lack the requisite sensitivity for in vivo multipopulation imaging. We describe high-performance green and red sensors, Ace-mNeon2 and VARNAM2, and their reverse response-polarity variants, pAce and pAceR. Our indicators enable 0.4-1 kHz voltage recordings from >50 neurons per field-of-view in awake mice and [~]30-min continuous imaging in flies. Using dual-polarity multiplexed imaging, we uncovered behavioral state-dependent interactions between distinct neocortical subclasses, as well as contributions to hippocampal field potentials from non-overlapping projection neuronal ensembles. By combining three mutually compatible indicators, we demonstrate concurrent triple-population voltage imaging. Our approach will empower investigations of the dynamic interplay between neuronal subclasses at single-spike resolution. One Sentence SummaryA new suite of voltage sensors enables simultaneous cellular-resolution activity imaging from multiple, targeted neuron-types in awake animals.

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bioRxiv2021

Rapid fluctuations in functional connectivity of cortical networks encode spontaneous behavior

Experimental work across a variety of species has demonstrated that spontaneously generated behaviors are robustly coupled to variation in neural activity within the cerebral cortex. Indeed, functional magnetic resonance imaging (fMRI) data suggest that functional connectivity in cortical networks varies across distinct behavioral states, providing for the dynamic reorganization of patterned activity. However, these studies generally lack the temporal resolution to establish links between cortical signals and the continuously varying fluctuations in spontaneous behavior typically observed in awake animals. Here, we took advantage of recent developments in wide-field, mesoscopic calcium imaging to monitor neural activity across the neocortex of awake mice. We develop a novel "graph of graphs" approach to quantify rapidly time-varying functional connectivity and show that spontaneous behaviors are represented by fast changes in both the activity and correlational structure of cortical network activity. Combining mesoscopic imaging with simultaneous cellular resolution 2-photon microscopy also demonstrated that the correlations among neighboring neurons and between local and large-scale networks also encodes behavior. Finally, the dynamic functional connectivity of mesoscale signals revealed subnetworks that are not predicted by traditional anatomical atlas-based parcellation of the cortex. These results provide new insight into how behavioral information is represented across the mammalian neocortex and demonstrate an analytical framework for investigating time-varying functional connectivity in neural networks.

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bioRxiv2021

A novel mouse model of focal limbic seizures that reproduces behavioral impairment associated with cortical slow wave activity

Patients with focal temporal lobe seizures often experience loss of consciousness. In humans, this loss of consciousness has been shown to be positively correlated with EEG neocortical slow waves, similar to those seen in non-REM sleep. Previous work in rat models of temporal lobe seizures suggests that decreased activity of subcortical arousal systems cause depressed cortical function during seizures. However, these studies were performed under light anesthesia, making it impossible to correlate behavior, and therefore consciousness, to electrophysiologic data. Further, the genetic and molecular toolkits allowing for precise study of the underlying neural circuitry are much more developed in mice than in rats. Here, we describe an awake-behaving, head-fixed mouse model of temporal lobe seizures with both spared and impaired behavior reflecting level of consciousness. Water-restricted mice were head-fixed on a running wheel and trained to associate an auditory stimulus to the delivery of a drop of water from a dispenser. To investigate the effect of seizures on behavior, seizures were electrically induced by stimulating either the left or right hippocampus via a chronically-implanted electrode, while mice were performing the task. Behavior was measured by monitoring lick responses to the auditory stimulus and running speed on the wheel. Further, local field potentials (LFP) signals were simultaneously recorded from hippocampus and orbitofrontal cortex (OFC). Induced focal seizures were 5-30s in duration, and repeatable for several weeks (n=20 animals). Behavioral responses showed a decrease in lick rate to auditory stimulus, and decreased running speed during seizures (p<0.01, n=20 animals). Interestingly, licking response to sound could vary from being impaired to normal during seizures. We found that behavioral impairment is correlated with large amplitude cortical slow-wave activity in frontal cortex, as seen in patients with temporal lobe seizures. These results suggest that induced focal limbic seizures in the mouse can impair consciousness and that the impaired consciousness is correlated with depressed cortical function resembling slow wave sleep. This novel mouse model has similar characteristics with previously studied rat models and human temporal lobe seizures. By leveraging the genetic and molecular techniques available in the mouse, this model can be used to further uncover fundamental mechanisms for loss of consciousness in focal seizures.

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bioRxiv2020

Dual color mesoscopic imaging reveals spatiotemporally heterogeneous coordination of cholinergic and neocortical activity.

Variation in an animals behavioral state is linked to fluctuations in brain activity and cognitive ability. In the neocortex, state-dependent control of circuit dynamics may reflect neuromodulatory influences including acetylcholine (ACh). While early literature suggested ACh exerts broad, homogeneous control over cortical function, recent evidence indicates potential anatomical and functional segregation of cholinergic signaling. Additionally, it is unclear whether states as defined by different behavioral markers reflect heterogeneous cholinergic and cortical network activity. We performed simultaneous, dual-color mesoscopic imaging of both ACh and calcium across the neocortex of awake mice to investigate their relationships with behavioral variables. We find that increasing arousal, categorized by different motor behaviors, is associated with spatiotemporally dynamic patterns of cholinergic release and enhanced large-scale network correlations. Overall, our findings demonstrate that ACh provides a highly dynamic and spatially heterogeneous signal that links fluctuations in behavior to functional reorganization of cortical networks.

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bioRxiv2020

Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics.

GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal, development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.

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bioRxiv2018

Spanning spatiotemporal scales with simultaneous mesoscopic Ca2+ imaging and functional MRI

Neuroscience encompasses the investigation of brain function across multiple spatiotemporal scales. Yet, most research is confined to Ca2+ one spatiotemporal milieu limiting the integration of knowledge across scales. Here we describe an imaging and analytic approach that spans spatiotemporal scales by combining simultaneous wide field mesoscopic 1-photon Ca2+ imaging and functional magnetic resonance imaging (fMRI) at 11.7T. Given the confined space within the magnet, that metal is prohibited, and the unique/conflicting needs of each methodology, these techniques have never before been combined. In addition to describing the new hardware and software, we present evoked and spontaneous activity measurements made in lightly anesthetized animals. We have three findings: (1) for both evoked and spontaneous activity the magnitude of the Ca2+ and fMRI signals show correspondence, (2) connectivity matrices derived from Ca2+ and fMRI measurements are stable throughout an imaging session, and (3) there is correspondence between Ca2+ and fMRI spontaneous activity patterns.

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