2004 — 2006 |
Sawtell, Nathaniel B |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Roles of Descending Feedback in Early Sensory Processing @ Oregon Health and Science University
DESCRIPTION (provided by applicant): Descending feedback is a prominent feature of vertebrate sensory systems, yet its importance for neural information processing is not well understood. The objective of this proposal is to determine functional roles of feedback in sensory processing at the levels of cells, local circuits, and behavior. These studies will be carried out in the electrosensory lobe (ELL) of mormyrid electric fish. The ELL is a cerebellum-like structure that integrates incoming sensory signals from electroreceptors with feedback from higher stages in the electrosensory system. Specific aim 1 will determine whether electrosensory feedback is used to generate predictions about the sensory environment. Specific aim 2 will determine whether feedback is crucial for the detection of weak electrosensory signals. Specific aim 3 will determine whether feedback controls spiketiming dependent synaptic plasticity in ELL. The proposed research will be conducted in vivo using intra- and extracellular recordings and behavioral measurements of electrosensory detection thresholds combined with inactivation of feedback. The results are expected to provide insights into how recurrent neural circuitry affects sensory processing.
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0.954 |
2006 — 2010 |
Sawtell, Nathaniel |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Descending Inputs and the Decoding of Temporally Encoded Sensory Information
Sensory information is often acquired through active exploration. Knowledge of the world is gained by exploring a complex surface with hands or a visual scene with eyes. Yet relatively little is known about how neurons encode sensory stimuli in the context of natural patterns of sensing behavior, or about how sensory processing regions in the brain distinguish properties of the external world from the sensory consequences of the animal's own behavior.
A particularly clear example of active sensing is found in mormyrid electric fish. Electric fish use an electrical sense to navigate and find prey in the dark by probing the environment by emitting brief electric organ discharge (EOD) pulses. Nearby objects perturb the electric field around the fish, and these perturbations are detected by electroreceptors in the fish's skin. Each receptor encodes changes in local field strength as small shifts in the precise timing of individual action potentials following the EOD. The fish thus obtains a sequence of "snapshots" of the world, in which information about surrounding objects is encoded in the timing of action potentials.
In nature, the frequency and regularity of this sequence of snapshots varies depending on the behavioral context, whether the fish is probing objects, foraging, or quietly resting. Interestingly, the frequency chosen by the fish has a clear effect on the timing of electroreceptor action potentials within each snapshot: higher rates shift spikes later, and lower rates shift spikes earlier. The size of these effects is comparable to the effects of small invertebrate prey on which these fish feed. How does the fish detect and capture prey when its own sensing behavior has such a strong effect on the sensory input?
This study provides opportunity to explore how sensory processing regions of the fish's brain resolves the ambiguity, and whether a change in the input from electroreceptors is due to an external stimulus or to the animal's own sensing behavior. Neurons at the first stage of electrosensory processing integrate input from electroreceptors with signals from other areas of the fish's brain linked to the motor command that evokes the EOD. Such motor command signals could, in principal, "undo" the effects of EOD rate on electroreceptor input.
The research is expected to lead to a better understanding of how animals use internal knowledge of their actions to distinguish properties of the external world from the sensory consequences of their own behavior. At a more cellular level, the experiements are also expected to lead to a better understanding of how information contained in the precise timing of action potentials is decoded or interpreted by neural circuits.
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0.915 |
2010 — 2014 |
Sawtell, Nathaniel |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Mechanisms For Sensory Prediction in a Cerebellum-Like Circuit
Complex nervous systems endow animals with the ability to predict, rather than merely react to, external events. Predictions allow past experience to guide action and are critical for both perception and movement. The goal of this research project is to understand the mechanisms that underlie predictive capacities at the levels of synapses, neurons, and circuits. The research takes advantage of a model system that is uniquely suited to address these issues. Electric fish generate weak electrical fields and, by sensing changes in these fields, are able to navigate and find prey in the dark. However to properly interpret these electrosensory signals, the fish must learn to predict and cancel out components of the input that are a direct result of the fish's own movement. The problem of differentiating self-generated from external sensory signals is a very general one, faced by all animals, including humans. A number of unique advantages have enabled major progress in understanding the neurobiological mechanisms for prediction and cancellation in the brains of electric fish. Interestingly, the neural circuitry for generating predictions in electric fish is highly similar to that of the mammalian cerebellum. Though known to be important for coordinated movement, the exact function of the cerebellum is not understood. Recently, several lines of evidence have suggested that the primate cerebellum may function to predict sensory events, similar to the known function of cerebellum-like circuits in fish. This project will yield novel insights into the functions of cerebellar circuitry and the neural mechanisms for predicting sensory events. Educational outreach will take advantage of the intriguing sensory and motor capacities of electric fish to provide students and teachers with an exciting entry point into biology and physics.
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0.915 |
2012 — 2015 |
Sawtell, Nathaniel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Roles For Granule Cells in Adaptive Processing in a Cerebellum-Like Circuit @ Columbia University Health Sciences
DESCRIPTION (provided by applicant): Prediction allows knowledge and experience to guide action and is critical for a range of sensory, motor, and cognitive functions. Failure to generate accurate predictions could contribute to neurological disorders such as autism and schizophrenia. This proposal takes advantage of an advantageous model system--a weakly electric fish--that will allow us to dissect the cellular and circuit mechanisms for predicting sensory events. Electric fish possess special receptors on their skin that allow them to detect weak electrical fields emitted by other animals in the water. This electrosense allows them to avoid predators and find prey in darkness. However, these fish also generate electrical fields of their own. Hence, a challenge for the electrosensory system is to distinguish between behaviorally relevant patterns of electrosensory input due to external events from those that are self-generated. Though particularly clear and accessible to study in electrosensory systems, this same problem faces all sensory systems. For over a century scientists and philosophers have puzzled over how we perceive a stable visual world despite the fact that visual input changes dramatically several times per second due to rapid movements of the eyes. One possible answer is that the brain generates predictions about changes in visual input that will result from our own movements and subtracts these predictions from the actual sensory input. Previous studies have shown that just such a process occurs in a region of the brain of electric fish that closely resembles the cerebellum. Previous studies have been able to directly demonstrate that predictions are formed via changes in the strength of connections between neurons, a process known as synaptic plasticity. Similar synaptic plasticity mechanisms exist in the mammalian cerebral cortex and cerebellum and are believed to underlie learning and memory. This proposal uses neural recordings and computational modeling to test the hypothesis that cerebellar granule cells generate representations of elapsed time that are critical for generating accurate predictions about temporal patterns of incoming electrosensory input. Though seminal theories proposed similar functions for granule cells in the context of cerebellar-dependent motor learning in mammals over 40 years ago, direct experimental support is still lacking. The proposed studies will provide novel insights into functions of cerebellar circuitry, neural representations of temporal information, and the neural mechanisms for predicting sensory events.
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0.915 |
2014 — 2017 |
Sawtell, Nathaniel Abbott, Laurence |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Crcns: From Sensation to Perception: Cellular and Circuit Mechanisms Underlying Prey Detection in An Electric Fish
A primary goal of neuroscience is to understand how the many components of the brain interact with each other to give rise to the remarkable capacities of perception, movement, and thinking exhibited by humans and other animals. For most brain regions, the parts list is too long and the function is poorly understood. This proposal takes advantage of an unusual animal--a fish that emits its own electrical field-- in which the brain structure is simple enough and the function sufficiently well understood, so that the detailed structure of neural circuits can be directly linked to function. The project combines high-resolution experimental measurements from individual components of the fish's brain with mathematical modeling to make such links. The specific goal of the proposal is to understand how changes in the strength of connections between neurons allows the fish to learn to ignore sensations produced by its own motor actions, so that the fish is better able to perceive tiny electrical fields generated by insect prey. The work entails extensive collaborative exchange between experimentalists and neural modelers, and will provide students at the undergraduate and graduate level with cross-disciplinary training. Additionally, science projects will be developed and taken to inner-city K-12 classrooms. Finally, the work has implications for our understanding of failures in the neural mechanisms that learn to distinguish self-generated from external sensory signals, a problem that is thought to occur in human neurological disorders such as schizophrenia.
The cerebellum-like electrosensory lobe (ELL) of mormyrid electric fish is an ideal model system for exploring how motor corollary discharge is used to predict self-generated sensory signals. Past work has produced a well-tested model in which spike timing-dependent synaptic plasticity sculpts well-described motor corollary discharge responses into a negative image of the sensory response to the fish's own electric organ discharge (EOD). The goal of this proposal is to extend this model from a description of the recordings of negative images in ELL to an understanding of the fish's ability to use this circuitry to detect the minute electrical signals generated by prey. The project will determine how ELL supports the detection of prey-like signals assessed from extracellular spike trains of identified neuron classes recorded at several key processing stages within the ELL. In parallel, models of ELL adaptive processing will be constructed to identify the essential features needed to account for the measured detection performance at both the neural and the behavioral level. Together, these closely coordinated experimental and theoretical efforts will provide a detailed explanation of how plasticity operating in a well-characterized circuit contributes to behavior.
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0.915 |
2016 — 2020 |
Sawtell, Nathaniel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms For Cancelling Self-Generated Sounds in the Mouse Dorsal Cochlear Nucleus @ Columbia University Health Sciences
Project Summary/Abstract Our own movements result in patterns of sensory receptor activation that may be similar or identical to those caused by external events. How does the brain make the critical distinction between self and other? Longstanding theories suggest that proprioceptive feedback or internal copies of motor commands, known as corollary discharge, could serve to predict and cancel out sensory input due to an animal?s own movements. However, it has been difficult to understand where and how such a process actually takes place within the brain. Some of the clearest insights come from cerebellum-like sensory structures associated with electrosensory processing in fish. Work in these systems, including that of the PI, has shown that synaptic plasticity acting on motor corollary discharge and proprioceptive information functions to predict and cancel out self-generated electrosensory inputs related to the fish?s own behavior. This proposal seeks to understand whether similar mechanisms are at work in the mammalian brain. Specifically, we focus on the dorsal cochlear nucleus (DCN)--a structure at the initial stage of mammalian auditory processing which strikingly resembles cerebellum-like structures in fish in terms of its circuitry and synaptic plasticity rules. We will use in vivo recordings from awake, behaving mice to test whether non-auditory, movement-related input to DCN functions to predict and cancel self-generated sounds associated with licking behavior. The proposed research is expected to provide fundamental insight into the computations performed by the DCN, including an answer to the longstanding question of why circuitry at the first stage of mammalian auditory processing resembles that of the cerebellum. More generally, this work will provide mechanistic insights into how the mammalian brain distinguishes between self-generated and external sources of sensory input. Finally, the common and in some cases debilitating condition of tinnitus?the persistent perception of sound in the absence of an external sound source?is associated with hyperactivity in DCN neurons and is hypothesized to be due, in part, to aberrant synaptic plasticity and somatosensory integration in DCN. This project seeks to understand the normal function of synaptic plasticity and somatosensory integration in DCN and hence may also provide insights into the pathophysiology of tinnitus.
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0.915 |
2016 — 2021 |
Sawtell, Nathaniel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms For Internal Models in a Cerebellum-Like Circuit @ Columbia University Health Sciences
Project Summary/Abstract Humans and other animals learn and store sophisticated models of the causal relationships that govern their interactions with the world. Such internal models are likely critical for transforming ambiguous and delayed sensory data into stable perceptions and coordinated movements. For example, distinguishing external sensory input from those that are self-generated could be accomplished via an internal model that predicts the sensory consequences of an animal?s own motor commands. Despite their potential importance for both normal brain function and neurological disorders, it has proven challenging to understand how internal models are actually implemented in neural circuits. This renewal proposal applies a combination of experimental and theoretical approaches to a model system?the weakly electric fish?with unique advantages for addressing this question. Our previous studies of electric fish were successful in developing a detailed mechanistic model of how neurons at the first stage of processing in the electrosensory lobe (ELL) predict and cancel out the effects of the fish?s own electric organ discharge (EOD). However, these studies considered a highly simplified version of the true problem facing the electrosensory system. Under natural conditions, electrosensory inputs vary moment-to-moment depending both on the movements of the fish (i.e. the position of the electric organ in the tail versus electroreceptors on the skin) and the temporal pattern of EOD motor commands emitted by the fish. Solving this problem requires a more complex internal model, akin to those believed to be generated in the mammalian brain. In addition, past models ignored key features of ELL circuitry, such as plasticity of inhibitory synapses, which likely play key functional roles (both in ELL and in other vertebrate brain circuits). By addressing these issues the proposed research will provide general insights into how neural circuits contribute to distinguishing self-generated from external stimuli. The proposed studies will also provide direct links between neural representations, well-defined circuitry, synaptic plasticity, and a behaviorally relevant systems level function. Though forging such links is a primary goal of neuroscience, there are still relatively few cases in which they can actually be made.
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0.915 |
2017 — 2020 |
Sawtell, Nathaniel |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Midbrain Electrosensory Processing in a Mormyrid Fish: Multimodal Integration, Recurrent Feedback, and Cerebellar Influence
Our ability to perceive, move, think, and remember arises from interactions between networks of neurons in the brain. Neuroscience research seeks to understand such interactions. However, in many cases, progress has been slow because the parts list is too long and the parts themselves are too complex. This project takes advantage of an unusual animal--a fish that emits its own electrical field, in which the individual brain structures are sufficiently simple and well-studied that their interactions can be understood in great detail. Specific goals of this project are to define the function of feedback or "backward" connections from higher to lower stages of sensory processing as well as the function of connections between the cerebellum and sensory processing regions. Feedback and cerebellar connections are believed to be critical for sensory processing in humans and have been implicated in neurological disorders such as autism, but our knowledge is sketchy and insufficient or designing treatments. By providing detailed information about such interactions in a simpler system, this project will serve as a foundation for understanding interactions in more complex systems such as the human brain. The investigator will use the resources developed from this project's research activities to improve science literacy and education regionally, nationally, and internationally.
By virtue of their tractable electrosensory and electromotor systems mormyrid fish have proven to be a valuable model system for linking structure and function in neural circuits. Studies of the first processing stage for the electrosense in the electrosensory lobe (ELL) have produced a fairly complete and well-tested model in which an experimentally measured form of spike timing-dependent synaptic plasticity acts on well-described motor corollary discharge responses to predict and cancel out self-generated sensory inputs. Anatomical studies have mapped central electrosensory pathways and behavioral studies have documented sophisticated electrolocation abilities that likely depend on higher-level neural processing. However physiological studies of higher stages of electrosensory processing are needed to link structure and function. The goal of this project is to provide the first in depth characterization of the midbrain lateral toral nucleus (NL)--the next major processing stage after ELL. The investigators' approach will include intracellular and extracellular electrophysiology in awake preparations, simultaneous behavioral measurements, and circuit manipulations. Proposed experiments will test specific hypotheses regarding NL function while at the same time addressing a number of general issues in neuroscience including multimodal integration, functions of recurrent feedback, and roles of the cerebellum in sensory processing.
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0.915 |