Biology subjects

Hendricks, W. D.

Publications and source records attributed to Hendricks, W. D..

6 recordsLinked to original sources

bioRxiv2025

Feature-tuned synaptic inputs to somatostatin interneurons drive context-dependent processing

Mapping neural computation onto the functional microarchitecture of sensory circuits is essential for understanding how brain circuits transform input signals into coherent percepts. Many higher-order perceptual processes emerge in the cortex, yet relatively little is known about how specific connectivity motifs give rise to these computations. To address this challenge, we combined single cell and population-level physiological recordings and perturbation methods to map a context-dependent cortical computation onto the synaptic microarchitecture of the mouse primary visual cortex (V1). We demonstrate a precise, recurrent circuit between cortical pyramidal cells (PCs) and somatostatin (SST) inhibitory interneurons that mediates context-driven figure/ground modulation in V1. Through a like-to-like connectivity rule from PCs and SSTs, this circuit explains SSTs visual encoding properties and their resulting impact on contextual modulation in V1. These findings reveal key synaptic and circuit mechanisms that may underlie the earliest stages of scene segmentation in the visual cortex. Moreover, they raise the notion that feature-specific excitatory-inhibitory microcircuitry from PC to SSTs could be a general strategy that the cortex exploits to give rise to higher level computations.

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↗

bioRxiv2019

Exercise-induced enhancement of synaptic functiontriggered by the inverse BAR protein, Mtss1L.

Exercise is a potent enhancer of learning and memory, yet we know little of the underlying mechanisms that likely include alterations in synaptic efficacy in the hippocampus. To address this issue, we exposed mice to a single episode of voluntary exercise, and permanently marked mature hippocampal dentate granule cells that were specifically activated during exercise using conditional Fos-TRAP mice. Only a few dentate granule cells were active at baseline, but two hours of voluntary exercise markedly increased the number of activated neurons. Activated neurons (Fos-TRAPed) showed an input-selective increase in dendritic spines and excitatory postsynaptic currents at 3 days post-exercise, indicative of exercise-induced structural plasticity. Laser-capture microdissection and RNASeq of activated neurons revealed that the most highly induced transcript was Mtss1L, a little-studied gene in the adult brain. Overexpression of Mtss1L in neurons increased spine density, leading us to hypothesize that its I-BAR domain initiated membrane curvature and dendritic spine formation. shRNA-mediated Mtss1L knockdown in vivo prevented the exercise-induced increases in spines and excitatory postsynaptic currents. Our results link short-term effects of exercise to activity-dependent expression of Mtss1L, which we propose as a novel effector of activity-dependent rearrangement of synapses. One Sentence SummarySingle episodes of voluntary exercise induced a functional increase in hippocampal synapses mediated by activity-dependent expression of the BAR protein Mtss1L, acting as a novel early effector of synapse formation.

neuroscience↗

bioRxiv2018

Early detonation by sprouted mossy fibers enables aberrant dentate network activity

In temporal lobe epilepsy, sprouting of hippocampal mossy fiber axons onto dentate granule cell dendrites creates a recurrent excitatory network. However, unlike mossy fibers projecting to CA3, sprouted mossy fiber synapses depress upon repetitive activation. Thus, despite their proximal location, large presynaptic terminals, and ability to excite target neurons, the impact of sprouted mossy fiber synapses on hippocampal hyperexcitability is unclear. We find that despite their short-term depression, single episodes of sprouted mossy fiber activation in hippocampal slices initiated bursts of recurrent polysynaptic excitation. Consistent with a contribution to network hyperexcitability, optogenetic activation of sprouted mossy fibers reliably triggered action potential firing in postsynaptic dentate granule cells after single light pulses. This pattern resulted in a shift in network recruitment dynamics to an \"early detonation\" mode and an increased probability of release compared to mossy fiber synapses in CA3. A lack of tonic adenosine-mediated inhibition contributed to the higher probability of glutamate release thus facilitating reverberant circuit activity.\n\nSignificance StatementSprouted mossy fibers are one of the hallmark histopathological findings in temporal lobe epilepsy. These fibers form recurrent excitatory synapses onto other dentate granule cells that display profound short-term depression. Here, however, we show that although these sprouted mossy fibers weaken substantially during repetitive activation, their initial high probability of glutamate release can activate reverberant network activity. Furthermore, we find that a lack of tonic adenosine inhibition enables this high probability of release and, consequently, recurrent network activity.

neuroscience↗