Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (33 results)

  • Article
  • Peer Reviewed
UC San Francisco Previously Published Works (2017)
Hebbian plasticity is widely considered to be the mechanism by which information can be coded and retained in neurons in the brain. Homeostatic plasticity moves the neuron back towards its original state following a perturbation, including perturbations produced by Hebbian plasticity. How then does homeostatic plasticity avoid erasing the Hebbian coded information? To understand how plasticity works in the brain, and therefore to understand learning, memory, sensory adaptation, development and recovery from injury, requires development of a theory of plasticity that integrates both forms of plasticity into a whole. In April 2016, a group of computational and experimental neuroscientists met in London at a discussion meeting hosted by the Royal Society to identify the critical questions in the field and to frame the research agenda for the next steps. Here, we provide a brief introduction to the papers arising from the meeting and highlight some of the themes to have emerged from the discussions.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.
    Cover page: Integrating Hebbian and homeostatic plasticity: introduction
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2014)
    Neurons in the visual cortex were first found to be exquisitely selective for particular properties of visual stimuli in anesthetized animals, including mice. Studies of alert mice in an apparatus that allowed them to stand or run revealed that locomotion causes a change in cortical state that dramatically increases the magnitude of responses in neurons of the visual cortex without altering selectivity, effectively changing the gain of sensory responses. Locomotion also dramatically enhances adult plasticity in the recovery from long-term visual deprivation. We have studied the elements and operation of the neural circuit responsible for the enhancement of activity and shown that it enhances plasticity even in mice not free to run. The circuit consists of projections ascending from the midbrain locomotor region (MLR) to the basal forebrain, activating cholinergic and perhaps other projections to excite inhibitory interneurons expressing vasoactive intestinal peptide (VIP) in the visual cortex. VIP cells activated by locomotion inhibit interneurons that express somatostatin (SST), thereby disinhibiting the excitatory principal neurons and allowing them to respond more strongly to effective visual stimuli. These findings reveal in alert animals how the ascending reticular activating system described in anesthetized animals 50 years ago operates to control cortical state.
      Cover page: A Neural Circuit That Controls Cortical State, Plasticity, and the Gain of Sensory Responses in Mouse
      • Thesis
      • Peer Reviewed
      UC San Francisco Electronic Theses and Dissertations (2022)

      Microglia, the innate immune cells of the brain, are exquisitely sensitive to dynamic changes in the brain environment. They respond to extracellular signals in order to promote synapse formation and turnover, respond to tissue damage and pathogens, and clean up dead or dying cells. Ultimately, microglia are professional phagocytes; so how do they decide what to eat? This dissertation examines multiple transcriptomically and functionally distinct subpopulations of phagocytic microglia that shape the developing brain. Chapter 1 is an introduction to microglia with an emphasis on phagocytosis. Chapter 2 provides an introduction to single-cell sequencing of microglia through a mini-review of two papers published in 2019. Chapter 3 characterizes two populations of microglia in the developing zebrafish brain, showing that neuron-engulfing and synapse-associated microglia have distinct transcriptomic and morphological states depending on their local environment. Chapter 4 identifies a new molecular signature associated with microglia that are actively engulfing whole neurons in the developing murine brain. These transient interferon-responsive microglia restrict the accumulation of damaged neurons. Chapter 5 discusses the implications of this work and how carefully designing single cell sequencing experiments in combination with in situ work allows the functional and transcriptomic characterization of transient and rare populations.

      • 1 supplemental ZIP
      Cover page: A multitude of meals and mechanisms: How microglia sculpt the brain
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2023)
      We have previously shown that recovery of visual responses to a deprived eye during the critical period in mouse primary visual cortex requires phosphorylation of the TrkB receptor for BDNF [M. Kaneko, J. L. Hanover, P. M. England, M. P. Stryker, Nat. Neurosci. 11, 497-504 (2008)]. We have now studied the temporal relationship between the production of mature BDNF and the recovery of visual responses under several different conditions. Visual cortical responses to an eye whose vision has been occluded for several days during the critical period and is then re-opened recover rapidly during binocular vision or much more slowly following reverse occlusion, when the previously intact fellow eye is occluded in a model of "patch therapy" for amblyopia. The time to recovery of visual responses differed by more than 18 h between these two procedures, but in each, the production of mature BDNF preceded the physiological recovery. These findings suggest that a spurt of BDNF production is permissive for the growth of connections serving the deprived eye to restore visual responses. Attenuation of recovery of deprived-eye responses by interference with TrkB receptor activation or reduction of BDNF production by interference with homeostatic synaptic scaling had effects consistent with this suggestion.
        Cover page: Production of brain-derived neurotrophic factor gates plasticity in developing visual cortex
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2017)
        Mechanisms thought of as homeostatic must exist to maintain neuronal activity in the brain within the dynamic range in which neurons can signal. Several distinct mechanisms have been demonstrated experimentally. Three mechanisms that act to restore levels of activity in the primary visual cortex of mice after occlusion and restoration of vision in one eye, which give rise to the phenomenon of ocular dominance plasticity, are discussed. The existence of different mechanisms raises the issue of how these mechanisms operate together to converge on the same set points of activity.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2018)
          Emerging technologies are now giving us unprecedented access to manipulate brain circuits, shedding new light on treatments for amblyopia. This research is identifying key circuit elements that control brain plasticity and highlight potential therapeutic targets to promote rewiring in the visual system during and beyond early life. Here, we explore how such recent advancements may guide future pharmacological, genetic, and behavioral approaches to treat amblyopia. We will discuss how animal research, which allows us to probe and tap into the underlying circuit and synaptic mechanisms, should best be used to guide therapeutic strategies. Uncovering cellular and molecular pathways that can be safely targeted to promote recovery may pave the way for effective new amblyopia treatments across the lifespan.
            Cover page: Amblyopia: New molecular/pharmacological and environmental approaches
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2014)
            Recovery from sensory deprivation is slow and incomplete in adult visual cortex. In this study, we show that visual stimulation during locomotion, which increases the gain of visual responses in primary visual cortex, dramatically enhances recovery in the
              • Thesis
              • Peer Reviewed
              UC San Francisco Electronic Theses and Dissertations (2020)

              To enable flexible behavior, the brain utilizes signals from across the sensory modalities, merging some streams while filtering out others in a context-dependent manner. These processes occur at many levels in the sensory hierarchy, but the cerebral cortex appears to play a prominent role in enabling dynamic use of crossmodal sensory information. This dissertation explores the interactions of auditory and visual sensory processing in the auditory cortex (ACtx) of the awake mouse using two experimental approaches. First, the influence of visual stimuli on neural firing in ACtx is investigated using multisite probes to sample activity across cortical layers. Visual stimuli elicit spiking responses in both primary and secondary ACtx. Through fluorescent dye electrode track tracing and optogenetic identification using layer-specific markers, these responses are revealed to be largely restricted to infragranular layers and particularly prominent in layer 6. Presentation of drifting visual gratings show that responses are not orientation-tuned, unlike visual cortex responses. The deepest cortical layers thus appear to be an important locus for crossmodal integration in ACtx. Second, to test the influence of modality-specific attention on ACtx stimulus processing, a novel audiovisual (AV) go/no-go rule-switching task for mice is presented. Translaminar ACtx extracellular recordings from mice performing the task show that attentional state modulates responses to AV stimuli. On average, single-unit firing rates (FRs) in deep and middle cortex are reduced during auditory attention in response to task-relevant stimuli, although a smaller population of units increases FRs. Pre-stimulus activity also decreases when behavior is guided by the auditory rule and appears to account for much of the change in stimulus-evoked activity. This general reduction in activity does not impair decoding with a PSTH-based pattern classifier, but instead increases mutual information encoding efficiency in the deep, putatively-excitatory neurons. Analysis of spectrotemporal receptive field (STRF) nonlinearities calculated from stimuli delivered between behavioral trials suggests that attending to sound increases the selectivity of neurons for STRF-defined sound features. These results suggest that modality-specific attention can act on ACtx in through rapid, context-dependent shifts in activity level as well as information processing.

                Cover page: Crossmodal influences in mouse auditory cortex during passive stimulation and an audiovisual behavior
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2017)
                Neurons in mouse primary visual cortex (V1) are selective for particular properties of visual stimuli. Locomotion causes a change in cortical state that leaves their selectivity unchanged but strengthens their responses. Both locomotion and the change in cortical state are thought to be initiated by projections from the mesencephalic locomotor region, the latter through a disinhibitory circuit in V1. By recording simultaneously from a large number of single neurons in alert mice viewing moving gratings, we investigated the relationship between locomotion and the information contained within the neural population. We found that locomotion improved encoding of visual stimuli in V1 by two mechanisms. First, locomotion-induced increases in firing rates enhanced the mutual information between visual stimuli and single neuron responses over a fixed window of time. Second, stimulus discriminability was improved, even for fixed population firing rates, because of a decrease in noise correlations across the population. These two mechanisms contributed differently to improvements in discriminability across cortical layers, with changes in firing rates most important in the upper layers and changes in noise correlations most important in layer V. Together, these changes resulted in a threefold to fivefold reduction in the time needed to precisely encode grating direction and orientation. These results support the hypothesis that cortical state shifts during locomotion to accommodate an increased load on the visual system when mice are moving.SIGNIFICANCE STATEMENT This paper contains three novel findings about the representation of information in neurons within the primary visual cortex of the mouse. First, we show that locomotion reduces by at least a factor of 3 the time needed for information to accumulate in the visual cortex that allows the distinction of different visual stimuli. Second, we show that the effect of locomotion is to increase information in cells of all layers of the visual cortex. Third, we show that the means by which information is enhanced by locomotion differs between the upper layers, where the major effect is the increasing of firing rates, and in layer V, where the major effect is the reduction in noise correlations.
                  Cover page: Locomotion Enhances Neural Encoding of Visual Stimuli in Mouse V1
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2017)
                  The responses of neurons in the visual cortex (V1) of adult mammals have long been thought to be stable over long periods. Here, we investigated whether repeated exposure to specific stimuli would enhance V1 visual responses in mice using intrinsic signal imaging through the intact skull and two-photon imaging of calcium signals in single neurons. Mice ran on Styrofoam balls floating on air while viewing one of three different, high-contrast visual stimuli. V1 responses to the stimuli that were viewed by the animal were specifically enhanced, while responses to other stimuli were unaffected. Similar exposure in stationary mice or in mice in which NMDA receptors were partially blocked did not significantly enhance responses. These findings indicate that stimulus-specific plasticity in the adult visual cortex depends on concurrent locomotion, presumably as a result of the high-gain state of the visual cortex induced by locomotion.SIGNIFICANCE STATEMENT We report a rapid and persistent increase in visual cortical responses to visual stimuli presented during locomotion in intact mice. We first used a method that is completely noninvasive to image intrinsic signals through the intact skull. We then measured the same effects on single neurons using two-photon calcium imaging and found that the increase in response to a particular stimulus produced by locomotion depends on how well the neuron is initially driven by the stimulus. To our knowledge, this is the first time such enhancement has been described in single neurons or using noninvasive measurements.
                    Cover page: Locomotion Induces Stimulus-Specific Response Enhancement in Adult Visual Cortex
                    Top