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Harnett, M.

Publications and source records attributed to Harnett, M..

6 recordsLinked to original sources

Vectorized instructive signals in cortical dendrites during a brain-computerinterface task

Vectorization of teaching signals is a key element of virtually all modern machine learning algorithms, including backpropagation, target propagation and reinforcement learning. Vectorization allows a scalable and computationally efficient solution to the credit assignment problem by tailoring instructive signals to individual neurons. Recent theoretical models have suggested that neural circuits could implement single-phase vectorized learning at the cellular level by processing feedforward and feedback information streams in separate dendritic compartments1-5. This presents a compelling, but untested, hypothesis for how cortical circuits could solve credit assignment in the brain. We leveraged a neurofeedback brain-computer interface (BCI) task with an experimenter-defined reward function to test for vectorized instructive signals in dendrites. We trained mice to modulate the activity of two spatially intermingled populations (4 or 5 neurons each) of layer 5 pyramidal neurons in the retrosplenial cortex to rotate a visual grating towards a target orientation while we recorded GCaMP activity from somas and corresponding distal apical dendrites. We observed that the relative magnitudes of somatic versus dendritic signals could be predicted using the activity of the surrounding network and contained information about task-related variables that could serve as instructive signals, including reward and error. The signs of these putative teaching signals both depended on the causal role of individual neurons in the task and predicted changes in overall activity over the course of learning. Furthermore, targeted optogenetic perturbation of these signals disrupted learning. These results provide the first biological evidence of a vectorized instructive signal in the brain, implemented via semi-independent computation in cortical dendrites, unveiling a potential mechanism for solving credit assignment in the brain.

neuroscience↗

Patch2MAP combines patch-clamp electrophysiology with super-resolution structural and protein imaging in identified single neurons without genetic modification

Recent developments in super-resolution microscopy have revolutionized the study of cell biology. However, dense tissues require exogenous protein expression for single cell morphological contrast. In the nervous system, many cell types and species of interest - particularly human - are not amenable to genetic modification and/or exhibit intricate anatomical specializations which make cellular delineation challenging. Here, we present a method for full morphological labeling of individual neurons from any species or cell type for subsequent cell-resolved protein analysis without genetic modification. Our method, which combines patch-clamp electrophysiology with epitope-preserving magnified analysis of proteome (eMAP), further allows for correlation of physiological properties with subcellular protein expression. We applied Patch2MAP to individual spiny synapses in human cortical pyramidal neurons and demonstrated that electrophysiological AMPA-to-NMDA receptor ratios correspond tightly to respective protein expression levels. Patch2MAP thus permits combined subcellular functional, anatomical, and proteomic analyses of any cell, opening new avenues for direct molecular investigation of the human brain in health and disease.

neuroscience↗

Highly synchronized cortical circuit dynamics mediate spontaneous pain

Cortical neural dynamics mediate information processing for the cerebral cortex, implicated in fundamental biological processes, such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes cortical network into an aberrant state, and if so, whether it can be brought back to a normal operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with robust spontaneous pain-like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized neural dynamics revealed by intravital two-photon calcium imaging. This synchronization was underpinned by local GABAergic interneuron hypoactivity. Pain-induced cortical synchronization could be attenuated by manipulating local S1 networks or clinically effective pain therapies. Specifically, both chemogenetic inhibition of pain-related c-Fos-expressing neurons, and selective activation of GABAergic interneurons, significantly attenuated S1 synchronization. Clinically effective pain therapies including carbamazepine and nerve root decompression could also dampen S1 synchronization. More importantly, restoring a normal range of neural dynamics, through attenuating pain-induced S1 synchronization, alleviated pain-like behavior. These results suggest spontaneous pain pushes S1 regional network into a synchronized state, whereas reversal of this synchronization alleviates pain.

neuroscience↗

Representation of Visual Landmarks in Retrosplenial Cortex

The process by which visual information is incorporated into the brains spatial framework to represent landmarks is poorly understood. Studies in humans and rodents suggest that retrosplenial cortex (RSC) plays a key role in these computations. We developed an RSC-dependent behavioral task in which head-fixed mice learned the spatial relationship between visual landmark cues and hidden reward locations. Two-photon imaging revealed that these cues served as dominant reference points for most task-active neurons and anchored the spatial code in RSC. Presenting the same environment but decoupled from mouse behavior degraded encoding fidelity. Analyzing visual and motor responses showed that landmark codes were the result of supralinear integration. Surprisingly, V1 axons recorded in RSC showed similar receptive fields. However, they were less modulated by task engagement, indicating that landmark representations in RSC are the result of local computations. Our data provide cellular- and network-level insight into how RSC represents landmarks.

neuroscience↗

An easy-to-assemble, robust, and lightweight drive implant for chronic tetrode recordings in freely moving animals

Tetrode arrays are the gold-standard method for neuronal recordings in many studies with behaving animals, especially for deep structures and chronic recordings. Here we outline an improved drive design for use in freely behaving animals. Our design makes use of recently developed technologies to reduce the complexity and build time of the drive while maintaining a low weight. The design also presents an improvement over many existing designs in terms of robustness and ease of use. We describe two variants: a 16 tetrode implant weighing [~]2 g for mice, bats, tree shrews and similar animals, and a 64 tetrode implant weighing [~]16 g for rats, and similar animals.These designs were co-developed and optimized alongside a new class of drive-mounted feature-rich amplifier boards with ultra-thin RF tethers, as described in an upcoming paper (Newman, Zhang et al., in prep). This design significantly improves the data yield of chronic electrophysiology experiments.

neuroscience↗

An animal-actuated rotational head-fixation system for 2-photon imaging during 2-d navigation

Understanding how the biology of the brain gives rise to the computations that drive behavior requires high fidelity, large scale, and subcellular measurements of neural activity. 2-photon microscopy is the primary tool that satisfies these requirements, particularly for measurements during behavior. However, this technique requires rigid head-fixation, constraining the behavioral repertoire of experimental subjects. Increasingly, complex task paradigms are being used to investigate the neural substrates of complex behaviors, including navigation of complex environments, resolving uncertainty between multiple outcomes, integrating unreliable information over time, and/or building internal models of the world. In rodents, planning and decision making processes are often expressed via head and body motion. This produces a significant limitation for head-fixed two-photon imaging. We therefore developed a system that overcomes a major problem of head-fixation: the lack of rotational vestibular input. The system measures rotational strain exerted by mice on the head restraint, which consequently drives a motor, rotating the constraint system and dissipating the strain. This permits mice to rotate their heads in the azimuthal plane with negligible inertia and friction. This stable rotating head-fixation system allows mice to explore physical or virtual 2-D environments. To demonstrate the performance of our system, we conducted 2-photon GCaMP6f imaging in somas and dendrites of pyramidal neurons in mouse retrosplenial cortex. We show that the subcellular resolution of the systems 2-photon imaging is comparable to that of conventional head-fixed experiments. Additionally, this system allows the attachment of heavy instrumentation to the animal, making it possible to extend the approach to large-scale electrophysiology experiments in the future. Our method enables the use of state-of-the-art imaging techniques while animals perform more complex and naturalistic behaviors than currently possible, with broad potential applications in systems neuroscience.

neuroscience↗