Biology subjects

Turrigiano, G. G.

Publications and source records attributed to Turrigiano, G. G..

14 recordsLinked to original sources

bioRxiv2025

Rapid prey capture learning drives a slow resetting of network activity in rodent binocular visual cortex

Neurons within primary visual cortex (V1) possess stable firing rate set points to which they faithfully return when perturbed by passive sensory manipulations. Chronic recordings in vivo suggest that these set points are present early in postnatal development and are stable through adulthood, raising the possibility that once they are established, they are largely immutable. Here we challenge this idea, using an ethological, vision-dependent prey capture learning paradigm in juvenile (critical period) rats. Juvenile rats rapidly (in one day) became proficient at catching crickets. This learning was impaired when V1 was inactivated, and was accompanied by an increase in the number of binocular V1 (V1b) neurons with firing reliably tied to specific behavioral epochs during hunts, indicating that hunting drives rapid functional plasticity within V1b. Remarkably, this rapid learning set in motion a slow, state-dependent increase in V1b firing, that began after learning was complete and persisted for days. This upward firing rate plasticity was gradual, occurred selectively during wake states, and in L2/3 was driven by a TNF-dependent increase in excitatory synapses and excitatory synaptic charge onto pyramidal neurons - all features of homeostatic forms of plasticity within V1. Finally, TNF inhibition administered after learning was complete diminished this increase in excitability and impaired the retention of hunting skills. Taken together, these data suggest that naturalistic learning in juvenile animals co-opts homeostatic forms of plasticity to reset firing rate setpoints within V1b, in a process that facilitates skill consolidation.

neuroscience↗

bioRxiv2025

Prey capture learning drives critical period-specific plasticity in mouse binocular visual cortex

Critical periods are developmental windows of high experience-dependent plasticity essential for the correct refinement of neuronal circuitry and function. While the consequences for the visual system of sensory deprivation during the critical period have been well-characterized, far less is known about the effects of enhanced sensory experience. Here, we use prey capture learning to assess structural and functional plasticity mediating visual learning in the primary visual cortex of critical period mice. We show that prey capture learning improves temporal frequency discrimination and drives a profound remodeling of visual circuitry through an increase in excitatory connectivity and spine turnover. This global and persistent rewiring is not observed in adult hunters and is mediated by TNF-dependent mechanisms. Our findings demonstrate that enhanced visual experience in a naturalistic paradigm during the critical period can drive structural plasticity to improve visual function, and promotes a long-lasting increase in spine dynamics that could enhance subsequent plasticity.

neuroscience↗

bioRxiv2024

Modular Arrangement of Synaptic and Intrinsic Homeostatic Plasticity within Visual Cortical Circuits

Neocortical circuits use synaptic and intrinsic forms of homeostatic plasticity to stabilize key features of network activity, but whether these different homeostatic mechanisms act redundantly, or can be independently recruited to stabilize different network features, is unknown. Here we used pharmacological and genetic perturbations both in vitro and in vivo to determine whether synaptic scaling and intrinsic homeostatic plasticity (IHP) are arranged and recruited in a hierarchical or modular manner within L2/3 pyramidal neurons in rodent V1. Surprisingly, although the expression of synaptic scaling and IHP was dependent on overlapping signaling pathways, they could be independently recruited by manipulating spiking activity or NMDAR signaling, respectively. Further, we found that changes in visual experience that affect NMDAR activation but not mean firing selectively trigger IHP, without recruiting synaptic scaling. These findings support a modular model in which synaptic and intrinsic homeostatic plasticity respond to and stabilize distinct aspects of network activity.

neuroscience↗

bioRxiv2022

Juvenile Shank3 KO mice adopt distinct hunting strategies during prey capture learning

Mice are opportunistic omnivores that readily learn to hunt and eat insects such as crickets. The details of how mice learn these behaviors and how these behaviors may differ in strains with altered neuroplasticity are unclear. We quantified the behavior of juvenile wild type and Shank3 knockout mice as they learned to hunt crickets during the critical period for ocular dominance plasticity. This stage involves heightened cortical plasticity including homeostatic synaptic scaling, which requires Shank3, a glutamatergic synaptic protein that, when mutated, produces Phelan-McDermid syndrome and is often comorbid with autism spectrum disorder (ASD). Both strains showed interest in examining live and dead crickets and learned to hunt. Shank 3 knockout mice took longer to become proficient, and, after 5 days, did not achieve the efficiency of wild type mice in either time-to-capture or distance-to-capture. Shank3 knockout mice also exhibited different characteristics when pursuing crickets that defied explanation as a simple motor deficit. Although both genotypes moved at the same average speed when approaching a cricket, Shank3 KO mice paused more often during approaches, did not begin final accelerations toward crickets as early, and did not close the distance gap to the cricket as quickly as wild type mice. These differences in Shank3 KO mice are reminiscent of some behavioral characteristics of individuals with ASD as they perform complex tasks, such as slower action initiation and completion. This paradigm will be useful for exploring the neural circuit mechanisms that underlie these learning and performance differences in monogenic ASD rodent models.

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bioRxiv2022

Strong Aversive Conditioning Triggers a Long-Lasting Generalized Aversion

Generalization is an adaptive mnemonic process in which an animal can leverage past learning experiences to navigate future scenarios, but overgeneralization is a hallmark feature of anxiety disorders. Therefore, understanding the synaptic plasticity mechanisms that govern memory generalization and its persistence is an important goal. Here, we demonstrate that strong CTA conditioning results in a long-lasting generalized aversion that persists for at least two weeks. Using brain slice electrophysiology and activity-dependent labeling of the conditioning-active neuronal ensemble within the gustatory cortex, we find that strong CTA conditioning induces a long-lasting increase in synaptic strengths that occurs uniformly across superficial and deep layers of GC. Repeated exposure to salt, the generalized tastant, causes a rapid attenuation of the generalized aversion that correlates with a reversal of the CTA-induced increases in synaptic strength. Unlike the uniform strengthening that happens across layers, reversal of the generalized aversion results in a more pronounced depression of synaptic strengths in superficial layers. Finally, the generalized aversion and its reversal do not impact the acquisition and maintenance of the aversion to the conditioned tastant (saccharin). The strong correlation between the generalized aversion and synaptic strengthening, and the reversal of both in superficial layers by repeated salt exposure, strongly suggests that the synaptic changes in superficial layers contribute to the formation and reversal of the generalized aversion. In contrast, the persistence of synaptic strengthening in deep layers correlates with the persistence of CTA. Taken together, our data suggest that layer-specific synaptic plasticity mechanisms separately govern the persistence and generalization of CTA memory.

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bioRxiv2021

A Bidirectional Switch in the Shank3 Phosphorylation State Biases Synapses toward Up or Down Scaling

Homeostatic synaptic plasticity requires widespread remodeling of synaptic signaling and scaffolding networks, but the role of posttranslational modifications in this process has not been systematically studied. Using deepscale, quantitative analysis of the phosphoproteome in mouse neocortical neurons, we found wide-spread and temporally complex changes during synaptic scaling up and down. We observed 424 bidirectionally modulated phosphosites that were strongly enriched for synapse-associated proteins, including S1539 in the ASD-associated synaptic scaffold protein Shank3. Using a parallel proteomic analysis performed on Shank3 isolated from rat neocortical neurons by immunoaffinity, we identified two sites that were hypo-phosphorylated during scaling up and hyper-phosphorylated during scaling down: one (rat S1615) that corresponded to S1539 in mouse, and a second highly conserved site, rat S1586. The phosphorylation status of these sites modified the synaptic localization of Shank3 during scaling protocols, and dephosphorylation of these sites via PP2A activity was essential for the maintenance of synaptic scaling up. Finally, phosphomimetic mutations at these sites prevented scaling up but not down, while phosphodeficient mutations prevented scaling down but not up. Thus, an activity-dependent switch between hypo- and hyperphosphorylation at S1586/ S1615 of Shank3 enables scaling up or down, respectively. Collectively our data show that activity-dependent phosphoproteome dynamics are important for the functional reconfiguration of synaptic scaffolds, and can bias synapses toward upward or downward homeostatic plasticity.

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bioRxiv2020

Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons

Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured neocortical pyramidal neurons, and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to excitatory neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses, and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

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bioRxiv2019

Stability of cortical synapses across sleep and wake

Sleep is important for brain plasticity, but its exact function remains mysterious. An influential but controversial idea is that a crucial function of sleep is to drive widespread downscaling of excitatory synaptic strengths. Here we used real-time sleep classification, ex vivo measurements of postsynaptic strength, and in vivo optogenetic monitoring of thalamocortical synaptic efficacy to ask whether sleep and wake states can constitutively drive changes in synaptic strength within the neocortex of juvenile rats. We found that miniature EPSC amplitudes onto L4 and L2/3 pyramidal neurons were stable across sleep and wake dense epochs in both primary visual (V1) and prefrontal cortex (PFC). Further, chronic monitoring of thalamocortical synaptic efficacy in V1 of freely behaving animals revealed stable responses across even prolonged periods of natural sleep and wake. Together these data demonstrate that neocortical synaptic strengths are remarkably stable across sleep and wake states, and provide strong evidence against the view that sleep drives widespread synaptic downscaling at neocortical synapses.

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bioRxiv2019

Sleep promotes downward firing rate homeostasis

Homeostatic plasticity is hypothesized to regulate neuronal activity around a stable set point to compensate for learning-related plasticity. This regulation is predicted to be bidirectional but only upward firing rate homeostasis (FRH) has been demonstrated in vivo. We combined chronic electrophysiology in freely behaving animals with a protocol that induces robust plasticity in primary visual cortex (V1) to induce downward FRH and show that neurons bidirectionally regulate firing rates around an individual set point. Downward FRH did not require N-methyl-D-aspartate receptor (NMDAR) signaling and was associated with homeostatic scaling down of synaptic strengths. Like upward FRH, downward FRH was gated by vigilance state, but in the opposite direction: it occurred during sleep and not during wake. In contrast, FR changes associated with Hebbian plasticity happened independently of sleep and wake. Thus, we find that sleeps impact on neuronal plasticity depends on the particular forms of plasticity that are engaged.

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bioRxiv2019

Homeostatic mechanisms regulate distinct aspects of cortical circuit dynamics

Homeostasis is indispensable to counteract the destabilizing effects of Hebbian plasticity. Although it is commonly assumed that homeostasis modulates synaptic strength, membrane excitability and firing rates, its role at the neural circuit and network level is unknown. Here, we identify changes in higher-order network properties of freely behaving rodents during prolonged visual deprivation. Strikingly, our data reveal that pairwise functional correlations and their structure are subject to homeostatic regulation. Using a computational model, we demonstrate that the interplay of different plasticity and homeostatic mechanisms can capture the initial drop and delayed recovery of firing rates and correlations observed experimentally. Moreover, our model indicates that synaptic scaling is crucial for the recovery of correlations and network structure, while intrinsic plasticity is essential for the rebound of firing rates, suggesting that synaptic scaling and intrinsic plasticity can serve distinct functions in homeostatically regulating network dynamics.

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bioRxiv2019

Rapid and Active Stabilization of Visual Cortical Firing Rates Across Light-Dark Transitions

The dynamics of neuronal firing during natural vision are poorly understood. Surprisingly, mean firing rates of neurons in primary visual cortex (V1) of freely behaving rodents are similar during prolonged periods of light and darkness, but it is unknown whether this reflects a slow adaptation to changes in natural visual input, or insensitivity to rapid changes in visual drive. Here we use chronic electrophysiology in freely behaving rats of either sex to follow individual V1 neurons across many dark-light (D-L) and light-dark (L-D) transitions. We show that, even on rapid timescales (1s to 10 min), neuronal activity was only weakly modulated by transitions that coincided with the expected 12h/12h light-dark cycle. In contrast, a larger subset of V1 neurons consistently responded to unexpected L-D and D-L transitions, and disruption of the regular L-D cycle with 60 hours of complete darkness induced a robust increase in V1 firing upon re-introduction of visual input. Thus, V1 neurons fire at similar rates in the presence or absence of natural stimuli, and significant changes in activity arise only transiently in response to unexpected changes in the visual environment. Further, although mean rates were similar in L and D, pairwise correlations were significantly stronger during natural vision, suggesting that information about natural scenes in V1 is more readily extractable from correlations than from individual firing rates. Together, our findings show that V1 firing rates are rapidly and actively stabilized during expected changes in visual input, and are remarkably stable at both short and long timescales.

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bioRxiv2018

Critical dynamics are a homeostatic set point of cortical networks in vivo.

The brain is constantly challenged by severely destabilizing forces: proteins turn over rapidly, Hebbian modifications alter and introduce positive feedback into networks, and environments change over many timescales. Homeostatic plasticity mechanisms, which operate via negative feedback, are believed to compensate for these changes and constrain neuronal activity to a firing rate (FR) set point1,2,3. For decades, it has been widely assumed that activity in neural networks is robust as a direct result of the widespread expression of FR homeostasis1,4. Here we reveal that network dynamics are stabilized independent of excitatory FR homeostasis and that cortical networks actively self-organize around an ideal computational regime.\n\nWe continuously tracked network spiking activity in the visual cortex (V1) of freely behaving rats for nine days. We found that, under baseline conditions, networks of excitatory neurons are robustly organized around criticality, a regime known to maximize information capacity and dynamic range. Monocular deprivation (MD) revealed a dissociation of excitatory FRs and network dynamics. MD immediately and severely disrupted network organization, which returned precisely to criticality over 48h. In contrast, both the excitatory FR drop and the subsequent FR recovery trailed the timecourse of network changes by more than 30h. Model investigations suggest a role for inhibitory neurons in maintaining critical dynamics. Collectively, these results show that complex activity in cortical circuits is actively maintained near criticality and that this organization is not explained by previously identified mechanisms of pyramidal neuron FR homeostasis.

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bioRxiv2018

Autism-associated Shank3 is essential for homeostatic plasticity and neuronal circuit stability

Mutations in Shank3 are strongly associated with autism spectrum disorders and circuit disfunction, but a unified view of how Shank3 loss disrupts circuit function and excitability is lacking. Stabilizing, homeostatic forms of synaptic and intrinsic plasticity are critical for preventing circuit hyper- or hypo-excitability, leading us to ask whether Shank3 loss perturbs circuits by disrupting homeostatic plasticity. We show that Shank3 loss abolishes synaptic and intrinsic homeostatic plasticity, which can be rescued by lithium(Li), a drug with therapeutic potential in human Shankopathies. Further, Shank3 loss in vivo severely compromises the ability of visual cortical circuits to recover from perturbations to sensory drive. Our findings suggest that the loss of homeostatic compensation is a critical endophenotype that can explain a range of circuit disfunctions in Shankopathies.

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bioRxiv2018

Sensory Deprivation Independently Regulates Neocortical Feedforward and Feedback Excitation-Inhibition Ratio

Brief (2-3d) monocular deprivation (MD) during the critical period induces a profound loss of responsiveness within layer 4 of primary visual cortex (V1). This has largely been ascribed to long-term depression (LTD) at thalamocortical synapses onto pyramidal neurons, while a contribution from intracortical inhibition has been controversial. Here we used optogenetics to probe feedforward thalamocortical and feedback intracortical excitation-inhibition (E-I) ratios following brief MD. While thalamocortical inputs onto pyramidal neurons were depressed, there was stronger depression onto PV+ interneurons, which shifted the thalamocortical-evoked E-I ratio toward excitation. In contrast, feedback intracortical E-I ratio was shifted toward inhibition, and a computational model of layer 4 demonstrated that these opposing shifts produced an overall suppression of layer 4 excitability. Thus, feedforward and feedback E-I ratios onto the same postsynaptic target can be independently regulated by visual experience, and enhanced feedback inhibition is the primary driving force behind loss of visual responsiveness.

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