Biology subjects

Zeiger, W. A.

Publications and source records attributed to Zeiger, W. A..

4 recordsLinked to original sources

bioRxiv2025

Cortical α-synuclein pathology induces cell autonomous neuronal hypoactivity and compensatory circuit changes in a model of early Lewy Body Dementia

Posterior cortical impairments in visuospatial/perceptual function are common non-motor symptoms of the Lewy Body Dementias (LBD) and are relatively specific for LBDs compared to other dementias. Across populations, cognitive impairments correlate with the presence of -synuclein (-syn) pathology in limbic and neocortical brain regions. However, the specific role that -syn pathology plays in driving cortical circuit dysfunction and cognitive impairment remains controversial. We hypothesized that inducing -syn pathology in primary visual cortex (V1) in mice would impair neuronal activity and encoding of visual information, leading to visuoperceptual impairments. To test this, we injected -syn pre-formed fibrils (PFF) into V1, causing the formation of sparse Lewy-like pathology. Using longitudinal in vivo two-photon (2P) calcium imaging over 6 months, we recorded visually evoked activity of pyramidal cells in layer 2/3 (L2/3) and quantified -syn pathology using C05-05, a fluorescent ligand that binds aggregated -syn. Measuring population activity, we found a greater percentage of neurons in PFF-injected mice were responsive to visual stimuli with lower direction selectivity compared to controls at 4-5 months post-injection (MPI). Neurons with somatic Lewy-like inclusions showed reduced activity compared to neighboring neurons without inclusions. Conversely, neurons without somatic inclusions showed increased activity, positively correlated with the local burden of -syn pathology. Using a coherent motion discrimination task, we found no impairments in visuoperceptual ability in PFF-injected mice. Our results demonstrate that -syn pathology leads to reductions in neuronal activity in cells with somatic inclusions and reciprocal changes in local population activity but does not impair visuoperceptual function. Reflecting the early stages of neocortical -syn pathology, our model provides a framework for future studies to better understand the heterogeneity of cognitive symptoms and -syn pathology across patients.

neuroscience↗

bioRxiv2025

Dynamic recruitment of PV interneurons in the somatosensory cortex induced by experience dependent plasticity

Adaptive circuit plasticity plays crucial roles in the brain during development, learning, sensory experience, and after injury. During chronic whisker trimming, a well-studied paradigm for inducing experience dependent plasticity, whisker representations in the somatosensory barrel cortex (S1BF) undergo remapping, with expansion of maps for spared whiskers and contraction of maps for trimmed whiskers. At the cellular level, excitatory pyramidal cells in Layer 2/3 shift their whisker tuning, increasing selectivity to spared whiskers and away from deprived whiskers. While these changes are well documented, the circuit mechanisms regulating experience-dependent plasticity remain incompletely characterized. Parvalbumin (PV) interneurons play important roles in regulating the spatial and temporal dynamics of sensory evoked activity in Pyr cells and have been implicated in the regulation of experience dependent plasticity in other cortical regions. However, there is little evidence as to how the sensory evoked activity of PV cells change in S1BF during whisker trimming or how those changes might affect cortical remapping. To address these questions, we used longitudinal in vivo two-photon (2P) calcium imaging of PV cells in S1BF before, during, and after inducing experience-dependent plasticity by whisker trimming. At baseline, we found that PV cells have spatially distributed responses to whisker deflections, responding best to the principal whisker of a given barrel and less frequently to surround whiskers in a distance-dependent manner. After whisker trimming, there is a substantial recruitment of PV cells responsive to the spared whisker in deprived, but not spared, barrels. Upon whisker regrowth, this recruitment is reversed, but changes in individual PV cell whisker selectivity can persist for weeks. To probe the potential casual effects of increased PV activity during whisker trimming, we used chemogenetics to acutely manipulate the activity of PV cells and found that modulating PV cell activity strongly affects sensory evoked responses in local Pyr and PV cells, as well as Somatostatin (SST) interneurons. In particular, increased PV cell activity strongly suppressed activity in all three cell types. Together, our results reveal dynamic changes in the spatial distribution and tuning of PV cells during experience dependent plasticity and suggest that increased PV cell activity could constrain the extent of potential cortical remapping in the adult S1BF.

neuroscience↗

bioRxiv2022

High sensitivity intrinsic optical signal imaging through flexible, low-cost adaptations of an upright microscope

Intrinsic optical signal imaging (IOSI) is a staple technique in modern neuroscience. Pioneered over thirty years ago, IOSI allows macroscopic mapping of neuronal activity throughout the cortex. The technique has been used to study sensory processing and experience-dependent plasticity, and is often used as an adjunctive procedure to localize cortical areas for subsequent targeting by other imaging or physiology techniques. Despite the ubiquity of IOSI in neuroscience there are few commercially available IOSI systems. As a result, investigators have typically resorted to building their own imaging systems. Over the years, simplified systems built on existing microscope platforms have been proposed. Still, these often require additional, sometimes costly, custom-built hardware, which presents challenges for investigators without significant experience in optics or microscopy design. Here we present a straightforward set of adaptations that can be applied to any standard upright microscope, using readily available, inexpensive, commercial parts for illumination, optics, and signal detection, that enables high sensitivity IOSI. Using these adaptations, we are able to readily map sensory-evoked signals across the somatosensory and visual cortex, including single-whisker barrel cortical activity maps in mice. We show that these IOSI maps are highly reproducible across animals and can be used to study plasticity mechanisms in the somatosensory cortex. We also provide open-source applications to control illumination and analyze raw data to generate activity maps. We anticipate these resources will be particularly useful for neuroscience investigators from broad technical backgrounds looking to add IOSI capabilities to an existing microscope on a budget.

neuroscience↗

bioRxiv2020

Plasticity after cortical stroke involves potentiating responses of pre-existing circuits but not functional remapping to new circuits

Functional recovery after stroke is thought to be mediated by adaptive circuit plasticity, whereby surviving neurons assume the roles of those that died. This "remapping" hypothesis is based on human brain mapping studies showing apparent reorganization of cortical sensorimotor maps and animal studies documenting molecular and structural changes that could support circuit rewiring. However, definitive evidence of remapping is lacking, and other studies have suggested that maladaptive plasticity mechanisms, such as enhanced inhibition in peri-infarct cortex, might actually limit plasticity after stroke. Here we sought to directly test whether neurons can change their response selectivity after a stroke that destroys a single barrel (C1) within mouse primary somatosensory cortex. Using multimodal in vivo imaging approaches, including two-photon calcium imaging to longitudinally record sensory-evoked activity in peri-infarct cortex before and after stroke, we found no evidence to support the remapping hypothesis. In an attempt to promote plasticity via rehabilitation, we also tested the effects of forced use therapy by plucking all whiskers except the C1 whisker. Again, we failed to detect an increase in the number of C1 whisker-responsive neurons in surrounding barrels even 2 months after stroke. Instead, we found that forced use therapy potentiated sensory-evoked responses in a pool of surviving neurons that were already C1 whisker responsive by significantly increasing the reliability of their responses. Together, our results argue against the long-held theory of functional remapping after stroke, but support a plausible circuit-based mechanism for how rehabilitation may improve recovery of function.

neuroscience↗