Biology subjects

Oldenburg, I. A.

Publications and source records attributed to Oldenburg, I. A..

7 recordsLinked to original sources

bioRxiv2026

Design Tradeoffs in High Resolution, Large Field-of-View 3D All-Optical Control of Neural Circuits

Multiphoton holographic optogenetics is an emerging technology that offers the ability to probe neural circuits with unprecedented temporal and spatial precision. When combined with in vivo imaging, it enables a host of experiments that were not previously possible. While this approach grows in popularity, the one-size-fits-all approach of most microscopes leads to systems that are not optimized for many experimental paradigms. Focusing on scanless temporally focused holographic optogenetic approaches, we explore the tradeoffs between resolution and field of view in different microscope designs. We show that simple changes in optical elements and lens order can create systems with both improved accessible range and resolution. Taking advantage of newer, high NA, 2P-optimized, low-magnification objectives, we demonstrate cellular-resolution holographic control over neurons separated by more than 1.4 mm in a single hologram, significantly expanding the spatial extent accessible for simultaneous neural manipulation in a conventional microscope. These changes are built upon a simple framework that leverages head-to-head system comparisons as a critical approach for evaluating the true advantages and limitations of an optical design, which could be incorporated into a wide variety of microscopes.

neuroscience↗

bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗

bioRxiv2026

The Importance of Synchrony in the Neural Control of Movement

Throughout the mammalian cortex, populations of neurons must work together to enact behaviors. While population recordings in motor cortex have revealed many aspects of when neurons fire during behaviors, limitations in causal experiments have made it difficult to identify which features of neural activity directly drive movements and which do not. Here, we explicitly test the principles of neural coding using high temporal precision multiphoton holographic optogenetics in the motor cortex. We show that activation of a small number (50-75) of Layer 2/3 excitatory neurons in the motor cortex is sufficient to drive movements. The efficacy of stimulation-driven movement depends on the state of the local circuit, and, to a lesser extent, the identity of which neurons are stimulated. We test whether evoked activity is acting through a rate code or a timing code by holding the firing rate and cell identities constant while varying the millisecond precise timing of activation. We find an unexpected and strong dependence on inter-cell synchrony when evoking movements. This neural synchrony recruits distinct patterns of recurrent excitation and inhibition. These findings provide evidence that the timing code, more so than the rate code, drives motor output.

neuroscience↗

bioRxiv2022

The logic of recurrent circuits in the primary visual cortex

Recurrent cortical activity sculpts visual perception by refining, amplifying, or suppressing incoming visual signals. Despite the importance of recurrent circuits for cortical processing, the basic rules that govern how nearby cortical neurons influence each other remains enigmatic. We used two-photon holographic optogenetics to activate ensembles of neurons in Layer 2/3 of the primary visual cortex (V1) in the absence of external stimuli to isolate the impact of local recurrence from external inputs. We find that the spatial arrangement and the stimulus feature preference of both the stimulated and the target ensemble jointly determine the net effect of recurrent activity, defining the cortical activity patterns that drive competition versus facilitation in L2/3 circuits. Computational modeling suggests that a combination of highly local recurrent excitatory connectivity and selective convergence onto inhibitory neurons give rise to these principles of recurrent activity. Our data and modeling reveal that recurrent activity can have varied impact, but a logic emerges through an understanding of the precise spatial distribution and feature preference of the multicellular pattern of activity.

neuroscience↗

bioRxiv2021

Multifunctional Cre-dependent transgenic mice for high-precision all-optical interrogation of neural circuits

Determining which features of the neural code drive perception and behavior requires the ability to simultaneous read out and write in neural activity patterns with high precision across many neurons. All-optical systems that combine two photon (2p) calcium imaging and targeted 2p photostimulation enable the activation of specific, functionally defined groups of neurons in behaving animals. However, these techniques do not yet have the ability to reveal how the specific distribution of firing rates across a relevant neural population mediates neural computation and behavior. The key technical obstacle is the inability to transform single-cell calcium signals into accurate estimates of firing rate changes and then write in these cell-specific firing rate changes to each individual neuron in a targeted population. To overcome this challenge, we made two advances: first we introduce a new genetic line of mice for robust Cre-dependent co-expression of a high-performance calcium indicator and a potent soma-targeted microbial opsin. Second, using this line, we developed a pipeline that enables the read-out and write-in of precise population vectors of neural activity across a targeted group of neurons. The combination of the new multifunctional transgenic line and the photostimulation paradigm offer a powerful and convenient platform for investigating the neural codes of computation and behavior. It may prove particularly useful for probing causal features of the geometry of neural representations where the ability to directly control the topology of population activity is essential.

neuroscience↗

bioRxiv2021

High performance microbial opsins for spatially and temporally precise perturbations of large neuronal networks

Patterned optogenetic activation of defined neuronal populations in the intact brain can reveal fundamental aspects of the neural codes of perception and behavior. The biophysical properties of existing optogenetic tools, however, constrain the scale, speed, and fidelity of precise optical control. Here we use structure-guided mutagenesis to engineer opsins that exhibit very high potency while retaining fast kinetics. These new opsins enable large-scale, temporally and spatially precise control of population neural activity in vivo and in vitro. We benchmark these new opsins against existing optogenetics tools with whole-cell electrophysiology and all-optical physiology and provide a detailed biophysical characterization of a diverse family of microbial opsins under two-photon illumination. This establishes a toolkit and a resource for matching the optimal opsin to the goals and constraints of patterned optogenetics experiments. Finally, by combining these new opsins with optimized procedures for cell-specific holographic photo-stimulation, we demonstrate the simultaneous co-activation of several hundred spatially defined neurons with a single hologram, and nearly double that number by temporally interleaving holograms at fast rates. These newly engineered opsins substantially extend the capabilities of patterned illumination optogenetic paradigms for addressing neural circuits and behavior.

neuroscience↗

bioRxiv2020

Spatial integration during active tactile sensation drives elementary shape perception

Active haptic sensation is critical for object identification and manipulation, such as for tool use in humans, or prey capture in rodents. The neural circuit basis for recognizing objects through active touch alone is poorly understood. To address this gap, we combined optogenetics, two photon imaging, and high-speed behavioral tracking in mice solving a novel surface orientation discrimination task with their whiskers. We found that orientation discrimination required animals to summate input from multiple whiskers specifically along the whisker arc. Many animals discriminated the orientation of the stimulus per se, as their performance was invariant to the specific location of the presented stimulus. Two photon imaging showed that populations of neurons in the barrel cortex encoded each of the discriminated orientations, and this coding depended on integration over the whisker array. Finally, acute optogenetic inactivation of the barrel cortex strongly impaired surface orientation discrimination, and even cell-type specific optogenetic suppression of layer 4 excitatory neurons degraded performance, implying a role for superficial layers in this computation. These data suggest a model in which spatial summation over an active haptic array generates representations of an objects surface orientations. These computations may facilitate the encoding of complex three-dimensional objects during active exploration.

neuroscience↗