Biology subjects

Kastner, D. B.

Publications and source records attributed to Kastner, D. B..

12 recordsLinked to original sources

bioRxiv2025

Partial Input Loss Differentially Modifies Neural Pathways

Following input loss from degeneration, injury, and/or aging, downstream circuits undergo modifications that can impact neural computations. How neural computations across different pathways are affected by common input loss remain understudied. To leverage known cell types, well-defined circuitry, and molecular tools, we use the mouse retina to show how multiple pathways adjust their functional properties differently to common input loss and further locate these changes within each pathway. Specifically, we asked if two OFF ganglion cell types, alpha OFF-sustained (AOFF-S) and OFF-transient (AOFF-T) cells, and their respective dominant presynaptic partners, type 2 and type 3a cone bipolar cells, respond differentially to partial cone loss. We find that AOFF-T ganglion cells exhibit more circuit changes than AOFF-S ganglion cells, resulting in altered spatiotemporal tuning following partial cone loss. We show that the underlying mechanisms include changes in glutamatergic, GABAergic, and glycinergic circuits in the pathway of AOFF-T ganglion cells. In response to common input loss, our study finds different locations of circuit modifications across OFF pathways. These findings provide insight into how sensory pathways can compensate differentially to common input loss.

neuroscience↗

bioRxiv2024

Convergence of autism proteins at the cilium

Hundreds of high-confidence autism genes have been identified, yet the relevant etiological mechanisms remain unclear. Gene ontology analyses have repeatedly identified enrichment of proteins with annotated functions in gene expression regulation and neuronal communication. However, proteins are often pleiotropic and these annotations are inherently incomplete. Our recent autism functional genetics work has suggested that these genes may share a common mechanism at the cilium, a membrane-bound organelle critical for neurogenesis, brain patterning, and neuronal activity-all processes strongly implicated in autism. Moreover, autism commonly co-occurs with conditions that are known to involve ciliary-related pathologies, including congenital heart disease, hydrocephalus, and blindness. However, the role of autism genes at the cilium has not been systematically investigated. Here we demonstrate that autism proteins spanning disparate functional annotations converge in expression, localization, and function at cilia, and that patients with pathogenic variants in these genes have cilia-related co-occurring conditions and biomarkers of disrupted ciliary function. This degree of convergence among genes spanning diverse functional annotations strongly suggests that cilia are relevant to autism, as well as to commonly co-occurring conditions, and that this organelle should be explored further for therapeutic potential. One-Sentence SummaryAutism genes of diverse functional annotations converge at cilia, deepening our understanding of underlying autism biology and co-occurring conditions.

cell biology↗

bioRxiv2024

The choice-wide behavioral association study: data-driven identification of interpretable behavioral components

Behavior contains rich structure across many timescales. However, there is a dearth of methods to identify relevant components, especially over the longer periods required for learning and decision-making. Inspired by the goals and techniques of genome-wide association studies, we present a data-driven method--the choice-wide behavioral association study: CBAS--that systematically identifies such behavioral features. CBAS extracts sequences of actions or choices that either significantly differ between groups or correlate with a covariate of interest, using a powerful resampling-based method to correct for multiple comparisons. We illustrate CBAS through application to tasks performed by flies, rats and humans, showing that it provides unexpected and interpretable information in each case.

neuroscience↗

bioRxiv2021

Hippocampal replay reflects specific past experiences rather than a plan for subsequent choice

Executing memory-guided behavior requires both the storage of information about experience and the later recall of that information to inform choices. Awake hippocampal replay, when hippocampal neural ensembles briefly reactivate a representation related to prior experience, has been proposed to critically contribute to these memory-related processes. However, it remains unclear whether awake replay contributes to memory function by promoting the storage of past experiences, by facilitating planning based on an evaluation of those experiences, or both. We designed a dynamic spatial task which promotes replay before a memory-based choice and assessed how the content of replay related to past and future behavior. We found that replay content was decoupled from subsequent choice and instead was enriched for representations of previously rewarded locations and places that had not been recently visited, indicating a role in memory storage rather than in directly guiding subsequent behavior.

neuroscience↗

bioRxiv2020

How inhibitory neurons increase information transmission under threshold modulation

Modulation of neuronal thresholds is ubiquitous in the brain. Phenomena such as figure-ground segmentation, motion detection, stimulus anticipation and shifts in attention all involve changes in a neurons threshold based on signals from larger scales than its primary inputs. However, this modulation reduces the accuracy with which neurons can represent their primary inputs, creating a mystery as to why threshold modulation is so widespread in the brain. We find that modulation is less detrimental than other forms of neuronal variability and that its negative effects can be nearly completely eliminated if modulation is applied selectively to sparsely responding neurons in a circuit by inhibitory neurons. We verify these predictions in the retina where we find that inhibitory amacrine cells selectively deliver modulation signals to sparsely responding ganglion cell types. Our findings elucidate the central role that inhibitory neurons play in maximizing information transmission under modulation.

neuroscience↗

bioRxiv2020

Scalable method for micro-CT analysis enables large scale quantitative characterization of brain lesions and implants

Anatomic evaluation is an important aspect of many studies in neuroscience; however, it often lacks information about the three-dimensional structure of the brain. Micro-CT imaging provides an excellent, nondestructive, method for the evaluation of brain structure, but current applications to neurophysiological or lesions studies require removal of the skull and hazardous chemicals, dehydration or embedding, limiting their scalability and utility. Here we present a protocol using eosin in combination with bone decalcification to enhance contrast in the tissue and then employ monochromatic and propagation phase-contrast micro-CT imaging to enable the imaging of brain structure with the preservation of the surrounding skull. Instead of relying on descriptive, time-consuming, or subjective methods, we develop simple quantitative analyses to map the locations of recording electrodes and to characterize the presence and extent of brain lesions.

neuroscience↗

bioRxiv2019

Dynamic preferences account for inter-animal variability during the continual learning of a cognitive task

Individual animals perform tasks in different ways, yet the nature and origin of that variability is poorly understood. In the context of spatial memory tasks, variability is often interpreted as resulting from differences in memory ability, but the validity of this interpretation is seldom tested since we lack a systematic approach for identifying and understanding factors that make one animals behavior different than another. Here we identify such factors in the context of spatial alternation in rats, a task often described as relying solely on memory of past choices. We combine hypothesis-driven behavioral design and reinforcement learning modeling to identify spatial preferences that, when combined with memory, support learning of a spatial alternation task. Identifying these preferences allows us to capture differences among animals, including differences in overall learning ability. Our results show that to understand the complexity of behavior requires quantitative accounts of the preferences of each animal.

neuroscience↗

bioRxiv2019

Robust and replicable measurement for prepulse inhibition of the acoustic startle response

Measuring animal behavior in the context of experimental manipulation is critical for modeling and understanding neuro-psychiatric disease. Prepulse inhibition of the acoustic startle response (PPI) is a behavioral paradigm used extensively for this purpose, but the results of PPI studies are often inconsistent. As a result, the utility of this metric remains uncertain. Here we deconstruct the phenomenon of PPI. We first confirm several limitations of the traditional PPI metric, including that the underlying startle response has a non-Gaussian distribution and that the traditional PPI metric changes with different stimulus condition. We then develop a novel model that reveals PPI to be a combination of the previously appreciated scaling of the startle response, as well as a scaling of sound perception. Using our model, we find no evidence for differences in PPI in a rat model of Fragile-X Syndrome (FXS) compared to wild-type controls. These results in the rat provide a reliable methodology that could be used to clarify inconsistent PPI results in mice and humans. In addition, we find robust differences between wild-type male and female rats. Our model allows us to understand the nature of these differences, and we find that both the startle-scaling and sound-scaling components of PPI are a function of the baseline startle response. Males and females differ specifically in the startle-scaling, but not the sound-scaling, component of PPI. These findings establish a robust experimental and analytical approach that has the potential to provide a consistent biomarker of brain function.

animal behavior and cognition↗

bioRxiv2018

Deep learning models reveal internal structure and diverse computations in the retina under natural scenes

Understanding how the visual system encodes natural scenes is a fundamental goal of sensory neuroscience. We show here that a three-layer network model predicts the retinal response to natural scenes with an accuracy nearing the fundamental limits of predictability. The models internal structure is interpretable, in that model units are highly correlated with interneurons recorded separately and not used to fit the model. We further show the ethological relevance to natural visual processing of a diverse set of phenomena of complex motion encoding, adaptation and predictive coding. Our analysis uncovers a fast timescale of visual processing that is inaccessible directly from experimental data, showing unexpectedly that ganglion cells signal in distinct modes by rapidly (< 0.1 s) switching their selectivity for direction of motion, orientation, location and the sign of intensity. A new approach that decomposes ganglion cell responses into the contribution of interneurons reveals how the latent effects of parallel retinal circuits generate the response to any possible stimulus. These results reveal extremely flexible and rapid dynamics of the retinal code for natural visual stimuli, explaining the need for a large set of interneuron pathways to generate the dynamic neural code for natural scenes.

neuroscience↗

bioRxiv2017

Synchronous inhibitory pathways create both efficiency and diversity in the retina

Visual information is conveyed from the retina to the brain by a diverse set of retinal ganglion cells. Although they have differing nonlinear properties, nearly all ganglion cell receptive fields on average compute a difference in intensity across space and time using a region known as the classical or linear surround1,2, a property that improves information transmission about natural visual scenes3,4. The spatiotemporal visual features that create this fundamental property have not been quantitatively assigned to specific interneurons. Here we describe a generalizable causal approach using simultaneous intracellular and multielectrode recording to directly measure and manipulate the sensory feature conveyed by a neural pathway to a downstream neuron. Analyzing two inhibitory cell classes, horizontal cells and linear amacrine cells, we find that rather than transmitting different temporal features, the two inhibitory pathways act synchronously to create the salamander ganglion cell surround at different spatial scales. Using these measured visual features and theories of efficient coding, we computed a fitness landscape representing the information transmitted using different weightings of the two inhibitory pathways. This theoretical landscape revealed a ridge that maintains near-optimal information transmission while allowing for receptive field diversity. The ganglion cell population showed a striking match to this prediction, concentrating along this ridge across a wide range of positions using different weightings of amacrine or horizontal cell visual features. These results show how parallel neural pathways synthesize a sensory computation, and why this architecture achieves the potentially competing objectives of high information transmission of individual ganglion cells, and diversity among receptive fields.

neuroscience↗

bioRxiv2017

Two-stage adaptation of inhibition mediates predictive sensitization in the retina

A critical function of the nervous system is the prediction of future sensory input. One such predictive computation is retinal sensitization, a form of short-term plasticity seen in multiple species that elevates local sensitivity following strong local stimulation. Here we perform a causal circuit analysis of retinal sensitization using simultaneous intracellular and multielectrode recording in the salamander. We show, using direct current injection into inhibitory sustained amacrine cells that a decrease in amacrine transmission is necessary, sufficient and occurs at the right time and manner to cause sensitization in ganglion cells. Because of neural dynamics and nonlinear pathways, a computational model is essential to explain how a change in steady inhibitory transmission causes sensitization. Whereas adaptation of excitation removes an expected result in order to transmit novelty, adaptation of inhibition provides a general mechanism to enhance the sensitivity to the sensory feature conveyed by an inhibitory pathway, creating a prediction of future input.

neuroscience↗

bioRxiv2017

Adaptive feature detection from differential processing in parallel retinal pathways

To transmit information efficiently in a changing environment, the retina adapts to visual contrast by adjusting its gain, latency and mean response. Additionally, the temporal frequency selectivity, or bandwidth changes to encode the absolute intensity when the stimulus environment is noisy, and intensity differences when noise is low. We show that the On pathway of On-Off retinal amacrine and ganglion cells is required to change temporal bandwidth but not other adaptive properties. This remarkably specific adaptive mechanism arises from differential effects of contrast on the On and Off pathways. We analyzed a biophysical model fit only to a cell's membrane potential, and verified pharmacologically that it accurately revealed the two pathways. We conclude that changes in bandwidth arise mostly from differences in synaptic threshold in the two pathways, rather than differences in synaptic release dynamics. Different efficient codes are selected by different thresholds in two independently adapting neural pathways.

neuroscience↗