Biology subjects

Burkhalter, A.

Publications and source records attributed to Burkhalter, A..

7 recordsLinked to original sources

bioRxiv2025

Motor impairment and adaptation in a novel non-human primate model of internal capsule infarct

Loss of distal hand and finger control is among the most disabling consequences of stroke. Functional outcomes are typically worse when infarcts involve subcortical white matter tracts, particularly the internal capsule, yet most preclinical stroke models target cortical regions. To address this gap, we developed a non-human primate model of internal capsule infarct using stereotactically guided endothelin-1 injections to disrupt descending fibers from the primary motor cortex hand area. Serial structural and diffusion MRI, along with histology, confirmed subcortical infarcts centered on the targeted white matter region with no apparent cortical involvement. Motor function was assessed pre- and post-infarct using a joystick-based center-out task (proximal forelimb control) and a Kluver board task (distal forelimb control). Animals exhibited variable impairments in proximal function and consistent post-infarct deficits in distal function, including reduced contralesional hand use, longer retrieval time, and increased in-well digit flexions. One animal showed mild post-infarct impairment and the smallest lesion, highlighting that this model reflects inter-individual differences in infarct size and functional outcome as seen in human subcortical stroke. In contrast, the other two animals developed a compensatory wrist-extended posture on the Kluver board task by 4 weeks post-infarct, which stabilized the hand and enabled improved digit flexion. Incorporating this behavioral adaptation into statistical models improved prediction of motor performance. The observed adaptation may have drawn on spared corticospinal output pathways, allowing animals to re-engage pre-existing motor routines to perform the retrieval. While future studies may benefit from ethologically relevant tasks to further elucidate such adaptations, findings from this study recapitulate key features of human subcortical stroke, including persistent distal motor deficits and emergence of adaptive motor strategies. By combining precise lesioning, longitudinal imaging, and detailed behavioral analysis, this model provides a translationally oriented platform for studying white matter stroke mechanisms and evaluating interventions that promote functional recovery.

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bioRxiv2025

Laminar Architecture of a Decision Circuit in Orbitofrontal Cortex

During economic choice, different neurons in orbitofrontal cortex (OFC) encode individual offer values, the binary choice outcome, and the chosen value. Previous work suggests that these cell groups form a decision circuit, but the anatomical organization of this circuit is poorly understood. Using calcium imaging, we recorded from layer 2/3 (L2/3) and layer 5 (L5) of mice choosing between juice flavors. Decision variables were differentially represented across layers: juice-specific offer values and their spatial configuration were predominant in L2/3, while spatial offer values, chosen side, and chosen value were predominant in L5. Within each layer, functional cell groups were organized in clusters. The temporal dynamics of neural signals in the two layers indicated a combination of feed-forward and feed-back processes, and pointed to L5 as the locus for winner-take-all value comparison. These results reveal that economic decisions rely on a complex architecture distributed across layers of OFC.

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bioRxiv2025

Interdigitating Modules for Visual Processing During Locomotion and Rest in Mouse V1

Layer 1 of V1 has been shown to receive locomotion-related signals from the dorsal lateral geniculate (dLGN) and lateral posterior (LP) thalamic nuclei (Roth et al., 2016). Inputs from the dLGN terminate in M2+ patches while inputs from LP target M2- interpatches (DSouza et al., 2019) suggesting that motion related signals are processed in distinct networks. Here, we investigated by calcium imaging in head-fixed awake mice whether L2/3 neurons underneath L1 M2+ and M2- modules are differentially activated by locomotion, and whether distinct networks of feedback connections from higher cortical areas to L1 may contribute to these differences. We found that strongly locomotion-modulated cell clusters during visual stimulation were aligned with M2- interpatches, while weakly modulated cells clustered under M2+ patches. Unlike M2+ patch cells, pairs of M2- interpatch cells showed increased correlated variability of calcium transients when the sites in the visuotopic map were far apart, suggesting that activity is integrated across large parts of the visual field. Pathway tracing further suggests that strong locomotion modulation in L2/3 M2- interpatch cells of V1 relies on looped, like-to-like networks between apical dendrites of MOs-, PM- and RSP-projecting neurons and feedback input from these areas to L1. M2- interpatches receive strong inputs from SST neurons, suggesting that during locomotion these interneurons influence the firing of specific subnetworks by controlling the excitability of apical dendrites in M2- interpatches. eLife digestDuring body, head and eye movements, many cells in the visual system increase their firing rate in order to distinguish between self-generated and externally generated image motion. While progress has been made in determining the brain circuits and cell types underlying this state-dependent signal, it is not known whether movement-modulated cells in primary visual cortex (V1) are distributed randomly or are spatially clustered. Meier et al., found that locomotion modulation is greater in periodically spaced clusters of layer (L) 2/3, which are aligned with M2 muscarinic acetylcholine receptor-negative interpatches of L1. Cells aligned with interpatches have higher sensitivity to the direction of visual motion at high speed (Ji et al., 2015). Cell pairs between visuotopically distant interpatch clusters show increased response correlations, suggesting signal integration across large parts of the visual field. The results further demonstrate that L1 M2- interpatches are densely innervated by somatostatin (SST)-expressing neurons, are targets of apical dendrites of MOs-(secondary motor cortex), PM-(posteromedial area) and RSP-(posterior retrosplenial cortex)-projecting neurons and are recipients of inputs from these sources. This indicates that L1 interpatches in V1 are targets for non-retinal movement-related feedback signals.

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bioRxiv2024

The Representation of Decision Variables in Orbitofrontal Cortex is Longitudinally Stable

The computation and comparison of subjective values underlying economic choices rely on the orbitofrontal cortex (OFC). In this area, distinct groups of neurons encode the value of individual options, the binary choice outcome, and the chosen value. These variables capture both the input and the output of the choice process, suggesting that the cell groups found in OFC constitute the building blocks of a decision circuit. Here we show that this neural circuit is longitudinally stable. Using two-photon calcium imaging, we recorded from mice choosing between different juice flavors. Recordings of individual cells continued for up to 20 weeks. For each cell and each pair of sessions, we compared the activity profiles using cosine similarity, and we assessed whether the cell encoded the same variable in both sessions. These analyses revealed a high degree of stability and a modest representational drift. A quantitative estimate indicated this drift would not randomize the circuit within the animals lifetime.

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bioRxiv2020

Canonical and noncanonical features of the mouse visual cortical hierarchy

Neocortical circuit computations underlying active vision are performed by a distributed network of reciprocally connected, functionally specialized areas. Mouse visual cortex is a dense, hierarchically organized network, comprising subnetworks that form preferentially interconnected processing streams. To determine the detailed layout of the mouse visual hierarchy, laminar patterns formed by interareal axonal projections, originating in each of ten visual areas were analyzed. Reciprocally connected pairs of areas, and shared targets of pairs of source areas, exhibited structural features consistent with a hierarchical organization. Beta regression analyses, which estimated a continuous measure of hierarchical distance, indicated that the network comprises multiple hierarchies embedded within overlapping processing levels. Single unit recordings showed that within each processing stream, receptive field sizes typically increased with increasing hierarchical level; however, ventral stream areas showed overall larger receptive field diameters. Together, the results reveal canonical and noncanonical hierarchical network motifs in mouse visual cortex.

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bioRxiv2019

Spatial clustering of inhibition in mouse primary visual cortex

Whether mouse visual cortex contains orderly feature maps is debated. The overlapping pattern of geniculocortical (dLGN) inputs with M2 muscarinic acetylcholine receptor-rich patches in layer 1 (L1) suggests a non-random architecture. Here, we found that L1 inputs from the lateral posterior thalamus (LP) avoid patches and target interpatches. Channelrhodopsin-assisted mapping of EPSCs in L2/3 shows that the relative excitation of parvalbumin-expressing interneurons (PVs) and pyramidal neurons (PNs) by dLGN, LP and cortical feedback are distinct and depend on whether the neurons reside in clusters aligned with patches or interpatches. Paired recordings from PVs and PNs shows that unitary IPSCs are larger in interpatches than patches. The spatial clustering of inhibition is matched by dense clustering of PV-terminals in interpatches. The results show that the excitation/inhibition balance across V1 is organized into patch and interpatch subnetworks which receive distinct long-range inputs and are specialized for the processing of distinct spatiotemporal features.

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bioRxiv2017

The Mouse Cortical Interareal Network Reveals Well Defined Connectivity Profiles and an Ultra Dense Cortical Graph

The inter-areal wiring pattern of mouse cerebral cortex was analyzed in relation to an accurate parcellation of cortical areas. Twenty-seven retrograde tracer injections were made in 19 areas of a 41 area (plus 7 sub-area) parcellation of the mouse neo-, parahippocampal and perirhinal cortex. Flat mounts of the cortex and multiple histological markers enabled detailed counts of labeled neurons in individual areas. A weight index was determined for each area-to-area pathway based on the Fraction of Extrinsically Labeled Neurons (FLNe). Data analysis allowed cross species comparison with the macaque. Estimation of FLNe statistical variability based on repeat injections revealed high consistency across individuals and justifies using a single injection per area to characterize connectivity. The observed lognormal distribution of connections to each cortical area spanned 5 orders of magnitude and revealed a distinct connectivity profile for each area, analogous to that observed in macaque. The resulting graph has a density of 97% (i.e. 97% of connections that can exist do exist), considerably higher than the 66% density reported for the macaque. Our results provide more sharply defined connectivity profiles and a markedly higher graph density than shown in a recent probabilistic mouse connectome.

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