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Higley, M. J.

Publications and source records attributed to Higley, M. J..

11 recordsLinked to original sources

Learning Interpretable Switching Dynamics in Shared Neural-Behavioral Latent Space

Modern recording technologies enable simultaneous measurement of high-dimensional neural activity and rich behavioral variables, creating both an opportunity and a modeling challenge: identifying the shared latent structure that mediates the brain-behavior relationship and the underlying dynamics through which it evolves across behavioral states. Existing approaches focus on different parts of this challenge: shared representation learning methods identify neural-behavioral subspaces but typically do not model dynamical structure, while dynamical models capture temporal variation and discrete state transitions in neural activity, but do not explicitly disentangle shared neural-behavioral structure from modality-specific variability. We introduce Switching Shared Latent Dynamics (SSLD), a unified framework that learns a latent representation shared between neural activity and behavior and endows this shared space with nonlinear switching recurrent dynamics to reflect the hypothesis that behaviorally relevant neural representations exhibit structured dynamical changes across behavioral states. Complementary private latent variables capture modality-specific variability, providing a window into neural activity that does not directly interact with behavior. We evaluate SSLD on a simulated dataset and four diverse experimental datasets spanning species, brain regions, and recording modalities: monkey motor and premotor cortex during reaching, somatosensory cortex during a bump task, widefield calcium imaging across mouse dorsal cortex during (a) self-initiated decision-making and (b) spontaneous movements. Across all four datasets, SSLD accurately reconstructs neural and behavioral signals, recovers discrete states in the dynamics that align with experimentally defined behavioral epochs, and isolates behaviorally-relevant neural information in the shared latent while preserving private neural variability. Ablations confirm that shared representation learning, behavioral supervision, and switching dynamics each contribute to performance. SSLD offers an interpretable approach to modeling shared neural-behavioral dynamics that complements ongoing efforts toward foundation models for neuroscience.

neuroscience↗

Cortical synaptic vulnerabilities revealed in a α-synuclein aggregation model of Parkinson's disease

-Synuclein aggregates characterize -synucleinopathies, including Parkinsons disease and Dementia with Lewy bodies. A majority of people with these disorders experience cognitive decline, and its extent correlates with cortical -synuclein pathology. Mechanisms by which pathology targets cortical circuits remain to be understood so that the debilitating non-motor impairments can be addressed. Overt neuronal loss is not a major feature of cortical pathology, but a reduction of presynaptic sites has been reported at late stages of PD. We here define excitatory synapses as neuronal loci affected by -synuclein aggregation, showing that they are progressively lost, and identify temporal and spatial patterns of synaptic vulnerability. Results were obtained in a mouse model using intrastriatal injection of pre-formed -synuclein fibrils to template the aggregation of endogenous -synuclein in cortical neurons. Lewy neurite-like aggregates were predominantly observed in axons. Super-resolved imaging showed -synuclein aggregation within cortical synapses and revealed that synaptic aggregation is most severe proximal to Lewy neurite-like structures and linked to the earliest detectable loss of excitatory synapses. Excitatory synapses also exhibited ultrastructural aberrations, including a redistribution of pre- and post-synaptic protein clusters away from contact sites and reduced synaptic vesicle size. As pathology advanced, VGLUT1-positive intracortical synapses, enriched in -synuclein, were progressively vulnerable in this striatal seeding model, while VGLUT2-positive long-range synapses with minimal -synuclein were spared. Inhibitory synapses were not affected. In agreement with a disruptive role of synaptic -synuclein aggregation, super-resolved mesoscale imaging determined that synaptic but not non-synaptic -synuclein pathology is correlated with excitatory synapse loss. Physiological recordings confirmed impaired excitatory neurotransmission. Pathology propagation tracked cortical connectivity, with intra-column synapse loss correlated between interconnected layers V and II/III. Contralateral areas receiving projections from pathologic layer V also exhibited synapse loss. These findings reveal synapses as principal cellular loci of -synuclein pathology and define how molecular and circuit-based mechanisms underlie the cortical progression of synaptic pathology in -synucleinopathies.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

Retrosplenial inputs drive diverse visual representations in the medial entorhinal cortex

The ability of rodents to use visual cues for successful navigation and goal-directed behavior has been long appreciated, although the neural mechanisms supporting sensory representations in navigational circuits are largely unknown. Navigation is fundamentally dependent on the hippocampus and closely connected entorhinal cortex, whose neurons exhibit characteristic firing patterns corresponding to the animals location. The medial entorhinal cortex (MEC) receives direct projections from sensory areas in the neocortex, suggesting the ability to encode sensory information. To examine this possibility, we performed high-density recordings of MEC neurons in awake, head-fixed mice presented with simple visual stimuli and assessed the dynamics of sensory-evoked activity. We found a large fraction of neurons exhibited robust responses to visual input that shaped activity relative to ongoing network dynamics. Visually responsive cells could be separated into subgroups based on functional and molecular properties within deep layers of the dorsal MEC, suggesting diverse populations within the MEC contribute to sensory encoding. We then showed that optogenetic suppression of retrosplenial cortex afferents within the MEC strongly reduced visual responses. Overall, our results demonstrate the the MEC can encode simple visual cues in the environment that can contribute to neural representations of location necessary for accurate navigation.

neuroscience↗

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.

neuroscience↗

NMDAR-dependent emergence of behavioral representation in primary visual cortex

Neocortical sensory areas are generally thought to faithfully represent external stimuli. However, a growing body of evidence suggests that cortical networks exhibit considerable functional plasticity over multiple temporal scales, allowing them to modify their output to reflect ongoing behavioral demands. Nevertheless, the dynamics of sensory and non-sensory representations during acquisition of stimulus-guided behavior are not well understood. We performed longitudinal 2-photon imaging of activity in primary visual cortex (V1) of mice learning a conditioned eyeblink task. We found that both excitatory and inhibitory neurons robustly encode the visual stimulus throughout training despite a significant experience-dependent reduction in response magnitude. In contrast, both pyramidal neurons and parvalbumin-expressing interneurons exhibit emergence of behavioral representation during learning. The plasticity of visual response magnitude and behavioral representation is abolished following loss of NMDA-type glutamate receptors. Overall, our findings demonstrate that V1 networks can dynamically multiplex distinct behaviorally relevant representations over the course of learning.

neuroscience↗

Layer 5 circuits in V1 differentially control visuomotor behavior

Sensory areas of the mammalian neocortex are thought to act as distribution hubs, transmitting information about the external environment to various cortical and subcortical structures in order to generate adaptive behavior. However, the exact role of cortical circuits in sensory perception remains unclear. Within primary visual cortex (V1), various populations of pyramidal neurons (PNs) send axonal projections to distinct targets, suggesting multiple cellular networks that may be independently engaged during the generation of behavior. Here, we investigated whether PN subpopulations differentially support sensory-guided performance by training mice in a visual detection task based on eyeblink conditioning. Applying 2-photon calcium imaging and optogenetic manipulation of anatomically-defined PNs in behaving animals, we show that layer 5 corticopontine neurons strongly encode task information and are selectively necessary for performance. These results contrast with recent observations of operant behavior showing a limited role for the neocortex in sensory detection. Instead, our findings support a model in which target-specific cortical subnetworks form the basis for adaptive behavior by directing relevant information to downstream brain areas. Overall, this work highlights the potential for neurons to form physically interspersed but functionally segregated networks capable of parallel, independent control of perception and behavior.

neuroscience↗

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.

neuroscience↗

Input-specific NMDAR-dependent potentiation of dendritic GABAergic inhibition

Preservation of a balance between synaptic excitation and inhibition is critical for normal brain function. A number of homeostatic cellular mechanisms have been suggested to play a role in maintaining this balance, including long-term plasticity of GABAergic inhibitory synapses. Many previous studies have demonstrated a coupling of postsynaptic spiking with modification of perisomatic inhibition. Here, we demonstrate that activation of NMDA-type glutamate receptors leads to input-specific long-term potentiation of dendritic inhibition mediated by somatostatin-expressing interneurons. This form of plasticity is expressed postsynaptically and requires both CaMKII and the {beta}2-subunit of the GABA-A receptor. Importantly, this process may function to preserve dendritic inhibition, as in vivo loss of NMDAR signaling results in a selective weakening of dendritic inhibition. Overall, our results reveal a new mechanism for linking excitatory and inhibitory input in neuronal dendrites and provide novel insight into the homeostatic regulation of synaptic transmission in cortical circuits.

neuroscience↗

Potassium channels contribute to activity-dependent scaling of dendritic inhibition

GABAergic inhibition plays a critical role in the regulation of neuronal activity. In the neocortex, inhibitory interneurons that target the dendrites of pyramidal cells influence both electrical and biochemical postsynaptic signaling. Voltage-gated ion channels strongly shape dendritic excitability and the integration of excitatory inputs, but their contribution to GABAergic signaling is less well understood. By combining 2-photon calcium imaging and focal GABA uncaging, we show that voltage-gated potassium channels normally suppress the GABAergic inhibition of calcium signals evoked by back-propagating action potentials in dendritic spines and shafts of cortical pyramidal neurons. Moreover, the voltage-dependent inactivation of these channels leads to enhancement of dendritic calcium inhibition following somatic spiking. Computational modeling reveals that the enhancement of calcium inhibition involves an increase in action potential depolarization coupled with the nonlinear relationship between membrane voltage and calcium channel activation. Overall, our findings highlight the interaction between intrinsic and synaptic properties and reveal a novel mechanism for the activity-dependent scaling of GABAergic inhibition.\n\nSignificance StatementGABAergic inhibition potently regulates neuronal activity in the neocortex. How such inhibition interacts with the intrinsic electrophysiological properties of single neurons is not well-understood. Here we investigate the ability of voltage-gated potassium channels to regulate the impact of GABAergic inhibition in the dendrites of neocortical pyramidal neurons. Our results show that potassium channels normally reduce inhibition directed towards pyramidal neuron dendrites. However, these channels are inactivated by strong neuronal activity, leading to an enhancement of GABAergic potency and limiting the corresponding influx of dendritic calcium. Our findings illustrate a previously unappreciated relationship between neuronal excitability and GABAergic inhibition.

neuroscience↗