Biology subjects

Nassi, J. J.

Publications and source records attributed to Nassi, J. J..

4 recordsLinked to original sources

bioRxiv2022

Mechanisms underlying reshuffling of visual responses by optogenetic stimulation in mice and monkeys

The ability to optogenetically perturb neural circuits opens an unprecedented window into mechanisms governing circuit function. We analyzed and theoretically modeled neuronal responses to visual and optogenetic inputs in mouse and monkey V1. In both species, optogenetic stimulation of excitatory neurons strongly modulated the activity of single neurons, yet had weak or no effects on the distribution of firing rates across the population. Thus, the optogenetic inputs reshuffled firing rates across the network. Key statistics of mouse and monkey responses lay on a continuum, with mice/monkeys occupying the low/high rate regions, respectively. We show that neuronal reshuffling emerges generically in randomly connected excitatory/inhibitory networks, provided the coupling strength (combination of recurrent coupling and external input) is sufficient that powerful inhibitory feedback cancels the mean optogenetic input. A more realistic model, distinguishing tuned visual vs. untuned optogenetic input in a structured network, reduces the coupling strength needed to explain reshuffling.

neuroscience↗

bioRxiv2020

Head-mounted microendoscopic calcium imaging in dorsal premotor cortex of behaving rhesus macaque

A major effort is now underway across the brain sciences to identify, characterize and manipulate mesoscale neural circuits in order to elucidate the mechanisms underlying sensory perception, cognition and behavior. Optical imaging technologies, in conjunction with genetically encoded sensors and actuators, serve as important tools toward these goals, allowing access to large-scale genetically defined neuronal populations. In particular, one-photon miniature microscopes, coupled with genetically encoded calcium indicators and microendoscopic gradient-refractive index (GRIN) lenses, enable unprecedented readout of neural circuit dynamics in cortical and deep subcortical brain regions during active behavior in rodents. This has already led to breakthrough discoveries across a wide array of rodent brain regions and behaviors. However, in order to study the neural circuit mechanisms underlying more complex and clinically relevant human behaviors and cognitive functions, it is crucial to translate this technology to non-human primates. Here, we describe the first successful application of this technology in the rhesus macaque. We identified a viral strategy for robust expression of GCaMP, optimized a surgical protocol for microendoscope GRIN lens insertion, and created a chronic cranial chamber and lens mounting system for imaging in gyral cortex. Using these methods, we demonstrate the ability to perform plug-and-play, head-mounted recordings of cellular-resolution calcium dynamics from over 100 genetically-targeted neurons simultaneously in dorsal premotor cortex while the macaque performs a naturalistic motor reach task with the head unrestrained and freely moving. The recorded population of neurons exhibited calcium dynamics selective to the direction of reach, which we show can be used to decode the animals trial-by-trial motor behavior. Recordings were stable over several months, allowing us to longitudinally track large populations of individual neurons and monitor their relationship to motor behavior over time. Finally, we demonstrate the ability to conduct simultaneous, multi-site imaging in bilateral dorsal premotor cortices, offering an opportunity to study distributed networks underlying complex behavior and cognition. Together, this work establishes head-mounted microendoscopic calcium imaging in macaque as a powerful new approach for studying the neural circuit mechanisms underlying complex and clinically relevant behaviors, and promises to greatly advance our understanding of human brain function, as well as its dysfunction in neurological disease. HighlightsFirst demonstration of head-mounted microendoscopic calcium imaging in behaving macaque. Surgical protocols developed for preparing the animal for calcium imaging, including virus injections to express GCaMP and chronic implantation of a GRIN lens to enable optical access to gyral cortex. Proof of concept plug-and-play calcium imaging in behaving macaques with months long stable recording capability allowing populations of individual neurons to be tracked longitudinally. Bilateral calcium imaging from dorsal premotor cortex exhibited dynamics selective to the animals direction of reach and allowed decoding of the animals motor behavior

neuroscience↗

bioRxiv2018

Calcium imaging in freely-moving mice during electrical stimulation of deep brain structures

After decades of study in humans and animal models, there remains a lack of consensus regarding how the action of electrical stimulation on neuronal and non-neuronal elements - e.g. neuropil, cell bodies, glial cells, etc. - leads to the therapeutic effects of neuromodulation therapies. To further our understanding of neuromodulation therapies, there is a critical need for novel methodological approaches using state-of-the-art neuroscience tools to study neuromodulation therapy in preclinical models of disease. In this manuscript we outline one such approach combining chronic behaving single-photon microendoscope recordings in a pathological mouse model with electrical stimulation of a common deep brain stimulation (DBS) target. We describe in detail the steps necessary to realize this approach, as well as discuss key considerations for extending this experimental paradigm to other DBS targets for different therapeutic indications. Additionally, we make recommendations from our experience on implementing and validating the required combination of procedures that includes: the induction of a pathological model (6-OHDA model of Parkinsons disease) through an injection procedure, the injection of the viral vector to induce GCaMP expression, the implantation of the GRIN lens and stimulation electrode, and the installation of a baseplate for mounting the microendoscope. We proactively identify unique data analysis confounds occurring due to the combination of electrical stimulation and optical recordings and outline an approach to address these confounds. In order to validate the technical feasibility of this unique combination of experimental methods, we present data to demonstrate that 1) despite the complex multifaceted surgical procedures, chronic optical recordings of hundreds of cells combined with stimulation is achievable over week long periods 2) this approach enables measurement of differences in DBS evoked neural activity between anesthetized and awake conditions and 3) this combination of techniques can be used to measure electrical stimulation induced changes in neural activity during behavior in a pathological mouse model. These findings are presented to underscore the feasibility and potential utility of minimally constrained optical recordings to elucidate the mechanisms of DBS therapies in animal models of disease.

bioengineering↗

bioRxiv2018

Optogenetically induced low-frequency correlations impair perception

Deployment of covert attention to a spatial location can cause large decreases in low-frequency correlated variability among neurons in macaque area V4 whose receptive-fields lie at the attended location. It has been estimated that this reduction accounts for a substantial fraction of the attention-mediated improvement in sensory processing. These estimates depend on assumptions about how population signals are decoded and the conclusion that correlated variability impairs perception, is purely hypothetical. Here we test this proposal directly by optogenetically inducing low-frequency fluctuations, to see if this interferes with performance in an attention-demanding task. We find that low- frequency optical stimulation of neurons in V4 elevates correlations among pairs of neurons and impairs the animals ability to make fine sensory discriminations. Stimulation at higher frequencies does not impair performance, despite comparable modulation of neuronal responses. These results support the hypothesis that attention-dependent reductions in correlated variability contribute to improved perception of attended stimuli.

neuroscience↗