Biology subjects

Glickfeld, L. L.

Publications and source records attributed to Glickfeld, L. L..

8 recordsLinked to original sources

bioRxiv2026

CRISPR inhibition of activity-dependent Arc expression in the adult mouse brain has limited effects on plasticity in visual cortex and nucleus accumbens

Neuronal activity drives long-lasting change in circuit function by inducing the expression of gene products that modulate the function of synapses. Arc is one of the most robustly activity-regulated neuronal genes, being induced broadly in neurons by a wide range of physiologically-relevant stimuli. The ability of Arc to promote internalization of AMPA-type glutamate receptors plays an important role in activity-dependent refinement of synaptic connectivity during development. However, the consequences of Arc induction for circuit plasticity in the adult brain are less well understood. We reasoned that we could test the requirement for experience-induced Arc expression in downstream plasticities by disrupting regulatory elements that mediate the inducibility of Arc transcription. To achieve this goal, we developed and validated a CRISPR-based inhibition strategy to conditionally block stimulus-induced expression of Arc in specific regions of the brains of male and female adult mice in vivo. We show that recruiting transgenic dCas9-KRAB to decrease transcriptional activity of either the promoter or the synaptic activity-regulated enhancer of the Arc gene is sufficient to block Arc protein expression in visual cortex (V1) following light exposure or in the nucleus accumbens (NAc) following cocaine administration. However, loss of Arc in V1 failed to alter plasticity of orientation selectivity and loss of Arc in NAc did not block cocaine conditioned place preference or novel object recognition memory. These data show that the relationship between Arc induction and plasticity is not universal and suggest that additional contextual factors determine the functional consequences of Arc induction for plasticity. Significance StatementArc is a neuronal activity-regulated gene whose expression is robustly induced in the adult brain by a wide range of stimuli that drive plasticity. However, the functional requirements of Arc induction for brain plasticity are incompletely understood. Here, we show that we can use transgenic mice expressing the CRISPR-based transcriptional repressor dCas9-KRAB to block stimulus-induced expression of Arc in specific regions of the adult mouse brain. Despite highly effective inhibition of Arc induction, we found that many forms of plasticity remained intact. These data deepen understanding of the contextual importance of activity-induced Arc expression in the adult brain.

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bioRxiv2025

Synaptic dynamics govern spatial integration in mouse visual cortex

Neurons in primary visual cortex are often suppressed by stimuli extending beyond their receptive fields. This surround suppression is proposed to reduce the redundancy of encoding large stimuli and support scene segmentation. We find that surround suppression decreases firing rates in mouse primary visual cortex by accelerating the decay of visually-evoked responses and reducing response duration. The rapid decay of visual responses at large sizes is enhanced by increased contrast, reduced by locomotion, and invariant to stimulus orientation, consistent with the engagement of a network mechanism. While fast-spiking interneurons have faster dynamics relative to neighboring pyramidal cells, the dynamics of somatostatin-expressing interneurons are delayed. At the subthreshold level, the rapid decay of visual responses with increasing size is due to a delayed removal of both synaptic excitation and inhibition below baseline levels following visual input. We propose that the delayed activation of somatostatin-expressing interneurons drives a network-wide suppression and accelerates the decay of the visual response. Thus, these data identify a key role for synaptic network dynamics in regulating both spatial and temporal integration in mouse visual cortex.

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bioRxiv2024

Behavioral state and stimulus strength regulate the role of somatostatin interneurons in stabilizing network activity

Inhibition stabilization enables cortical circuits to encode sensory signals across diverse contexts. Somatostatin-expressing (SST) interneurons are well-suited for this role through their strong recurrent connectivity with excitatory pyramidal cells. We developed a cortical circuit model predicting that SST cells become increasingly important for stabilization as sensory input strengthens. We tested this prediction in mouse primary visual cortex by manipulating excitatory input to SST cells, a key parameter for inhibition stabilization, with a novel cell-type specific pharmacological method to selectively block glutamatergic receptors on SST cells. Consistent with our model predictions, we find antagonizing glutamatergic receptors drives a paradoxical facilitation of SST cells with increasing stimulus contrast. In addition, we find even stronger engagement of SST-dependent stabilization when the mice are aroused. Thus, we reveal that the role of SST cells in cortical processing gradually switches as a function of both input strength and behavioral state.

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bioRxiv2023

Input-specific synaptic depression shapes temporal integration in mouse visual cortex

Efficient sensory processing requires the nervous system to adjust to ongoing features of the environment. In primary visual cortex (V1), neuronal activity strongly depends on recent stimulus history. Existing models can explain effects of prolonged stimulus presentation, but remain insufficient for explaining effects observed after shorter durations commonly encountered under natural conditions. We investigated the mechanisms driving adaptation in response to brief (100 ms) stimuli in L2/3 V1 neurons by performing in vivo whole-cell recordings to measure membrane potential and synaptic inputs. We find that rapid adaptation is generated by stimulus-specific suppression of excitatory and inhibitory synaptic inputs. Targeted optogenetic experiments reveal that these synaptic effects are due to input-specific short-term depression of transmission between layers 4 and 2/3. Thus, distinct mechanisms are engaged following brief and prolonged stimulus presentation and together enable flexible control of sensory encoding across a wide range of time scales.

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bioRxiv2022

Thousandfold Cell-Specific Pharmacology of Neurotransmission

Cell-specific pharmaceutical technologies promise mechanistic insight into clinical drugs[-]those that treat, and often define, human disease. In particular, DART (drug acutely restricted by tethering) achieves genetically programmable control of drug concentration over cellular dimensions. The method is compatible with clinical pharmaceuticals and amenable to studies in behaving animals. Here, we describe DART.2, comprising three advances. First, we improve the efficiency of chemical capture, enabling cell-specific accumulation of drug to [~]3,000-times the ambient concentration in 15 min. Second, we develop tracer reagents, providing a behavior-independent measure of cellular target engagement in each animal. Third, we extend the method to positive allosteric modulators and outline design principles for this clinically significant class. We showcase the platform with four pharmaceuticals[-]two that weaken excitatory (AMPAR) or inhibitory (GABAAR) chemical neurotransmission, and two that strengthen these forms of synaptic communication. Across four labs, we tested reagents in the mouse cerebellum, basal ganglia, visual cortex, and retina. Collectively, we demonstrate robust, bidirectional editing of chemical neurotransmission. We provide for distribution of validated reagents, community design principles, and synthetic building blocks for application to diverse pharmaceuticals.

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bioRxiv2021

Feedforward mechanisms of masking in mouse V1

Sensory neurons not only encode stimuli that align with their receptive fields but are also modulated by context. For example, the responses of neurons in mouse primary visual cortex (V1) to gratings of their preferred orientation are modulated by the presence of superimposed orthogonal gratings ("plaids"). The effects of this modulation can be diverse: some neurons exhibit cross-orientation suppression while other neurons have larger responses to a plaid than its components. We investigated whether these diverse forms of masking could be explained by a unified circuit mechanism. We report that the suppression of cortical activity does not alter the effects of masking, ruling out cortical mechanisms. Instead, we demonstrate that the heterogeneity of plaid responses is explained by an interaction between stimulus geometry and orientation tuning. Highly selective neurons uniformly exhibit cross-orientation suppression, whereas in weakly-selective neurons masking depends on the spatial configuration of the stimulus, with effects transitioning systematically between suppression and facilitation. Thus, the diverse responses of mouse V1 neurons emerge as a consequence of the spatial structure of the afferent input to V1, with no need to invoke cortical interactions.

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bioRxiv2020

Distinct recruitment of feed-forward and recurrent pathways across higher-order areas of mouse visual cortex

Cortical visual processing transforms features of the external world into increasingly complex and specialized neuronal representations. These transformations arise in part through target-specific routing of information; however, within-area computations may also contribute to area-specific function. Here, we sought to determine whether higher-order visual cortical areas LM, AL, PM, and AM have specialized anatomical and physiological properties by using a combination of whole-cell recordings and optogenetic stimulation of V1 axons in vitro. We discovered area-specific differences in the strength of recruitment of interneurons through feed-forward and recurrent pathways, as well as differences in cell-intrinsic properties and interneuron densities. These differences were most striking when comparing across medial and lateral areas, suggesting that these areas have distinct profiles for net excitability and integration of V1 inputs. Thus, cortical areas are not defined simply by the information they receive, but also by area-specific circuit properties that enable specialized filtering of these inputs.

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bioRxiv2019

Separable codes for read-out of mouse primary visual cortex across attentional states

Attentional modulation of neuronal activity in sensory cortex could alter perception by enhancing the local representation of attended stimuli or its behavioral read-out downstream. We tested these hypotheses using a task in which mice are cued on interleaved trials to attend visual or auditory targets. Neurons in primary visual cortex (V1) that encode task stimuli have larger visually-evoked responses when attention is directed toward vision. To determine whether the attention-dependent changes in V1 reflect changes in representation or read-out, we decoded task stimuli and choices from population activity. Surprisingly, both visual and auditory choices can be decoded from V1, but decoding takes advantage of unique activity patterns across modalities. Furthermore, decoding of choices, but not stimuli, is impaired when attention is directed toward the opposite modality. The specific effect on choice suggests behavioral improvements with attention are largely due to targeted read-out of the most informative V1 neurons.

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