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Cell Rep. Author manuscript; available in PMC 2016 March 09. Published in final edited form as: Cell Rep. 2016 February 2; 14(4): 795–807. doi:10.1016/j.celrep.2015.12.068.
Information Coding Through Adaptive Gating of Synchronized Thalamic Bursting Clarissa J Whitmire1, Christian Waiblinger1,2,3, Cornelius Schwarz2,3, and Garrett B Stanley1 1
Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332
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2
Systems Neurophysiology, Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany 3
Department of Cognitive Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Summary
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It has been posited that the regulation of burst/tonic firing in the thalamus could function as a mechanism for controlling not only how much, but what kind of information is conveyed to downstream cortical targets. Yet how this gating mechanism is adaptively modulated on fast time scales by ongoing sensory inputs in rich sensory environments remains unknown. Using single unit recordings in the rat vibrissa thalamus (VPm), we found that the degree of bottom-up adaptation modulated thalamic burst/tonic firing as well as the synchronization of bursting across the thalamic population along a continuum for which the extremes facilitate detection or discrimination of sensory inputs. Optogenetic control of baseline membrane potential in thalamus further suggests that this regulation may result from an interplay between adaptive changes in thalamic membrane potential and synaptic drive from inputs to thalamus, setting the stage for an intricate control strategy upon which cortical computation is built.
Graphical Abstract
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Correspondence should be addressed to Professor Garrett B. Stanley, Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, 313 Ferst Drive, Atlanta, GA 30332, Phone: 404.385.5037, [email protected]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Author Contributions Conceptualization, C.J.W., C.W., C.S., G.S.; Methodology, C.J.W.; Investigation, C.J.W., C.W.; Writing – Original Draft, C.J.W., G.S.; Writing – Reviewing & Editing, C.J.W., C.W., C.S., G.S.;
Whitmire et al.
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Introduction
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The majority of our sensations travel from the periphery through the thalamus before reaching cortex, such that each sensory region of thalamus has a corresponding cortical projection. Despite the strategic positioning of this brain structure, surprisingly little is known about its ultimate function. While it is clear that the various nuclei of the thalamus play a vital role in high level functions such as attention, perception, and consciousness, as evidenced by lesioning of the thalamus (Schmahmann, 2003; Van Der Werf et al., 2000), it is unclear as to what active role it plays. Due to a preponderance of T-type calcium channels in this region, thalamic neurons are particularly prone to vacillate between burst and tonic firing modes in a state-dependent manner (Suzuki and Rogawski, 1989). Although thalamic bursting was originally associated with a disconnection between the cortex and the periphery (Steriade et al., 1993), it has been posited that regulation of burst firing in the thalamus may serve as a dynamic gating mechanism for controlling information flow to cortex (Crick, 1984; Lesica and Stanley, 2004; Lesica et al., 2006; Sherman, 1996; Wang et al., 2007). It has been established that the continuous transition between burst and tonic firing is determined by both the subthreshold membrane potential of the neuron as well as the ongoing synaptic activity (Mukherjee and Kaplan, 1995; Wolfart et al., 2005). However, what is not at all understood is how the transition between burst and tonic firing modes is modulated in a dynamic sensory environment, how this is coordinated across the neuronal population, and how this thalamic state transition affects information transmission. The rapid adaptation of functional properties in response to changes in sensory stimulation, over a range of temporal and spatial scales, is common to all sensory modalities (Wark et al., 2007). For example, a simple change in statistics of a sensory signal, such as the stimulus contrast, can lead to a cascade of changes in sensory encoding, from gain rescaling (Fairhall et al., 2001; Shapley and Victor, 1979) to fundamental alterations to the feature selectivity of
Cell Rep. Author manuscript; available in PMC 2016 March 09.
Whitmire et al.
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Author Manuscript
sensory neurons (Lesica et al., 2007), which are even more pronounced when considering differential adaptation across neuronal populations. This has led to the proposal that this form of adaptation serves to enhance information transmission in the dynamic sensory environments (Sharpee et al., 2006). In the thalamocortical pathway, the functional role of adaptation in modulating the spike timing of sensory-evoked activity within and across thalamic neurons has a particularly strong impact on the activation of their downstream cortical targets that rely on weak, but highly convergent inputs from the thalamus (Bruno and Sakmann, 2006). We have recently shown that adaptation serves to desynchronize the firing activity of thalamic neurons (Ollerenshaw et al., 2014; Wang et al., 2010), but the interaction between adaptive mechanisms and the regulation of synchronized bursting across thalamic inputs to cortex is not at all understood, yet could serve as a robust mechanism for gating information flow as a function of bottom up and top down influences.
Author Manuscript
Here, we demonstrate a direct link between ongoing bottom-up sensory adaptation and the modulation of feature-evoked bursting in the ventral posterior medial (VPm) region of the thalamus in the vibrissa pathway of the rat. Baseline recordings were obtained under fentanyl anesthesia, corresponding to a relatively hyperpolarized thalamic state, such that adaptation transitioned the thalamus from a burst to a tonic firing mode. Using optogenetic depolarization to directly modulate thalamus, we identified a graded, sustained depolarization of thalamic neurons as the likely mechanism by which adapting stimuli modulate evoked bursting activity, working in concert with changes in synaptic drive, to gate thalamic activity. From the perspective of timing-based ideal observer analysis of thalamic spiking activity, sensory adaptation led to reduced detectability, but enhanced discriminability at an intermediate level of adaptation. Furthermore, paired recordings demonstrated a reduction in not only synchronous firing, but synchronous burst firing with more profound adaptation. Therefore, the regulation of stimulus-driven synchronized bursting may be a critical mechanism for gating peripheral inputs that form sensory cortical representations.
Author Manuscript
Results Adaptation shifts thalamus from burst to tonic firing
Author Manuscript
We recorded single unit activity in the ventral posteromedial (VPm) nucleus of the rat vibrissal lemniscal pathway in response to single whisker stimuli with or without optogenetic modulation of the thalamic membrane potential under fentanyl-cocktail anesthesia (Fig 1A). The sensory stimulus consisted of an ethologically relevant feature embedded in an ongoing adapting background stimulus (Fig 1B; Whisker Angle, see Experimental Procedures). The shape of the feature was designed to mimic high velocity deflections, or stick-slip events, that match the feature selectivity of thalamic neurons in this pathway (Petersen et al., 2008; Ritt et al., 2008; Wolfe et al., 2008), while the amplitudes of the feature were chosen to span the behavioral range of feature detectability from ongoing sensory stimulation (Stüttgen et al., 2006) (AF = 0, 1, 2, 4, 8, 16°; rise time = 5 ms). The frequency content of the adapting noise stimulus spanned 0-200Hz to sample relevant whisker stimulation frequencies (Lottem and Azouz, 2008) within the physical limitations of the whisker stimulator, while the amplitude of the noise were set at levels perceptible to the
Cell Rep. Author manuscript; available in PMC 2016 March 09.
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animal (AN = 0, 0.07, 0.17, 0.34, 0.68, 2.75, 5.5°), as ascertained in a separate study (Waiblinger et al., 2015b). Note that we have demonstrated that this form of rapid adaptation is very similar in the presence of repetitive/periodic whisker stimulation and “white noise” stimulation, depending primarily on the overall power in the adapting stimulus (Zheng et al., 2015), and is distinctly different from forms of stimulus-specific adaptation. While sensory adaptation has many definitions/meanings within specific sensory modalities, the universal ability of the pathway to adapt to ongoing changes in the stimulus statistics has been demonstrated in auditory (Dean et al., 2005), visual (Fairhall et al., 2001), and somatosensory (Maravall et al., 2007) pathways. Here, the statistics of the adapting stimulus were systematically varied to investigate the changes in feature selectivity in the presence of varying statistical properties of the adapting stimulus.
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Thalamic neurons responded strongly when stimulus features were presented in isolation (Not Adapted condition), but the stimulus feature elicited fewer spikes when surrounded by an adapting noise stimulus (Adapted condition), even when the amplitude of the adaptive noise stimulus was relatively small compared to the amplitude of the feature (shown for an example neuron in Figure 1B; AF = 8°, AN = 0.32°). In this example neuron, the Not Adapted feature response was strong (as defined by the number of elicited spikes) and temporally precise (as defined by the first spike latency jitter) on nearly every trial (Figure 1B; Not Adapted). In contrast, the Adapted neural response for this example neuron showed greater background firing due to the evoked response from the adapting stimulation and reduced feature-evoked activity (Figure 1B; Adapted). Across cells, the background firing activity due to the evoked response from the adapting stimulus was increased relative to the spontaneous firing in the Not Adapted condition (p = 1.18e-5, paired Wilcoxon signed-rank test, data not shown). The response to the stimulus feature (RF), defined as the number of spikes in a 10 millisecond window following feature presentation (see Supplemental Experimental Procedures), increased with increasing feature amplitude across cells (Figure 1C solid, Not Adapted; n = 26 cells), but was significantly attenuated in the Adapted condition (Figure 1C dashed, Adapted; n = 26 cells, *p
Cell Rep. Author manuscript; available in PMC 2016 March 09. Published in final edited form as: Cell Rep. 2016 February 2; 14(4): 795–807. doi:10.1016/j.celrep.2015.12.068.
Information Coding Through Adaptive Gating of Synchronized Thalamic Bursting Clarissa J Whitmire1, Christian Waiblinger1,2,3, Cornelius Schwarz2,3, and Garrett B Stanley1 1
Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332
Author Manuscript
2
Systems Neurophysiology, Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany 3
Department of Cognitive Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Summary
Author Manuscript
It has been posited that the regulation of burst/tonic firing in the thalamus could function as a mechanism for controlling not only how much, but what kind of information is conveyed to downstream cortical targets. Yet how this gating mechanism is adaptively modulated on fast time scales by ongoing sensory inputs in rich sensory environments remains unknown. Using single unit recordings in the rat vibrissa thalamus (VPm), we found that the degree of bottom-up adaptation modulated thalamic burst/tonic firing as well as the synchronization of bursting across the thalamic population along a continuum for which the extremes facilitate detection or discrimination of sensory inputs. Optogenetic control of baseline membrane potential in thalamus further suggests that this regulation may result from an interplay between adaptive changes in thalamic membrane potential and synaptic drive from inputs to thalamus, setting the stage for an intricate control strategy upon which cortical computation is built.
Graphical Abstract
Author Manuscript
Correspondence should be addressed to Professor Garrett B. Stanley, Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, 313 Ferst Drive, Atlanta, GA 30332, Phone: 404.385.5037, [email protected]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Author Contributions Conceptualization, C.J.W., C.W., C.S., G.S.; Methodology, C.J.W.; Investigation, C.J.W., C.W.; Writing – Original Draft, C.J.W., G.S.; Writing – Reviewing & Editing, C.J.W., C.W., C.S., G.S.;
Whitmire et al.
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Introduction
Author Manuscript Author Manuscript
The majority of our sensations travel from the periphery through the thalamus before reaching cortex, such that each sensory region of thalamus has a corresponding cortical projection. Despite the strategic positioning of this brain structure, surprisingly little is known about its ultimate function. While it is clear that the various nuclei of the thalamus play a vital role in high level functions such as attention, perception, and consciousness, as evidenced by lesioning of the thalamus (Schmahmann, 2003; Van Der Werf et al., 2000), it is unclear as to what active role it plays. Due to a preponderance of T-type calcium channels in this region, thalamic neurons are particularly prone to vacillate between burst and tonic firing modes in a state-dependent manner (Suzuki and Rogawski, 1989). Although thalamic bursting was originally associated with a disconnection between the cortex and the periphery (Steriade et al., 1993), it has been posited that regulation of burst firing in the thalamus may serve as a dynamic gating mechanism for controlling information flow to cortex (Crick, 1984; Lesica and Stanley, 2004; Lesica et al., 2006; Sherman, 1996; Wang et al., 2007). It has been established that the continuous transition between burst and tonic firing is determined by both the subthreshold membrane potential of the neuron as well as the ongoing synaptic activity (Mukherjee and Kaplan, 1995; Wolfart et al., 2005). However, what is not at all understood is how the transition between burst and tonic firing modes is modulated in a dynamic sensory environment, how this is coordinated across the neuronal population, and how this thalamic state transition affects information transmission. The rapid adaptation of functional properties in response to changes in sensory stimulation, over a range of temporal and spatial scales, is common to all sensory modalities (Wark et al., 2007). For example, a simple change in statistics of a sensory signal, such as the stimulus contrast, can lead to a cascade of changes in sensory encoding, from gain rescaling (Fairhall et al., 2001; Shapley and Victor, 1979) to fundamental alterations to the feature selectivity of
Cell Rep. Author manuscript; available in PMC 2016 March 09.
Whitmire et al.
Page 3
Author Manuscript
sensory neurons (Lesica et al., 2007), which are even more pronounced when considering differential adaptation across neuronal populations. This has led to the proposal that this form of adaptation serves to enhance information transmission in the dynamic sensory environments (Sharpee et al., 2006). In the thalamocortical pathway, the functional role of adaptation in modulating the spike timing of sensory-evoked activity within and across thalamic neurons has a particularly strong impact on the activation of their downstream cortical targets that rely on weak, but highly convergent inputs from the thalamus (Bruno and Sakmann, 2006). We have recently shown that adaptation serves to desynchronize the firing activity of thalamic neurons (Ollerenshaw et al., 2014; Wang et al., 2010), but the interaction between adaptive mechanisms and the regulation of synchronized bursting across thalamic inputs to cortex is not at all understood, yet could serve as a robust mechanism for gating information flow as a function of bottom up and top down influences.
Author Manuscript
Here, we demonstrate a direct link between ongoing bottom-up sensory adaptation and the modulation of feature-evoked bursting in the ventral posterior medial (VPm) region of the thalamus in the vibrissa pathway of the rat. Baseline recordings were obtained under fentanyl anesthesia, corresponding to a relatively hyperpolarized thalamic state, such that adaptation transitioned the thalamus from a burst to a tonic firing mode. Using optogenetic depolarization to directly modulate thalamus, we identified a graded, sustained depolarization of thalamic neurons as the likely mechanism by which adapting stimuli modulate evoked bursting activity, working in concert with changes in synaptic drive, to gate thalamic activity. From the perspective of timing-based ideal observer analysis of thalamic spiking activity, sensory adaptation led to reduced detectability, but enhanced discriminability at an intermediate level of adaptation. Furthermore, paired recordings demonstrated a reduction in not only synchronous firing, but synchronous burst firing with more profound adaptation. Therefore, the regulation of stimulus-driven synchronized bursting may be a critical mechanism for gating peripheral inputs that form sensory cortical representations.
Author Manuscript
Results Adaptation shifts thalamus from burst to tonic firing
Author Manuscript
We recorded single unit activity in the ventral posteromedial (VPm) nucleus of the rat vibrissal lemniscal pathway in response to single whisker stimuli with or without optogenetic modulation of the thalamic membrane potential under fentanyl-cocktail anesthesia (Fig 1A). The sensory stimulus consisted of an ethologically relevant feature embedded in an ongoing adapting background stimulus (Fig 1B; Whisker Angle, see Experimental Procedures). The shape of the feature was designed to mimic high velocity deflections, or stick-slip events, that match the feature selectivity of thalamic neurons in this pathway (Petersen et al., 2008; Ritt et al., 2008; Wolfe et al., 2008), while the amplitudes of the feature were chosen to span the behavioral range of feature detectability from ongoing sensory stimulation (Stüttgen et al., 2006) (AF = 0, 1, 2, 4, 8, 16°; rise time = 5 ms). The frequency content of the adapting noise stimulus spanned 0-200Hz to sample relevant whisker stimulation frequencies (Lottem and Azouz, 2008) within the physical limitations of the whisker stimulator, while the amplitude of the noise were set at levels perceptible to the
Cell Rep. Author manuscript; available in PMC 2016 March 09.
Whitmire et al.
Page 4
Author Manuscript
animal (AN = 0, 0.07, 0.17, 0.34, 0.68, 2.75, 5.5°), as ascertained in a separate study (Waiblinger et al., 2015b). Note that we have demonstrated that this form of rapid adaptation is very similar in the presence of repetitive/periodic whisker stimulation and “white noise” stimulation, depending primarily on the overall power in the adapting stimulus (Zheng et al., 2015), and is distinctly different from forms of stimulus-specific adaptation. While sensory adaptation has many definitions/meanings within specific sensory modalities, the universal ability of the pathway to adapt to ongoing changes in the stimulus statistics has been demonstrated in auditory (Dean et al., 2005), visual (Fairhall et al., 2001), and somatosensory (Maravall et al., 2007) pathways. Here, the statistics of the adapting stimulus were systematically varied to investigate the changes in feature selectivity in the presence of varying statistical properties of the adapting stimulus.
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Thalamic neurons responded strongly when stimulus features were presented in isolation (Not Adapted condition), but the stimulus feature elicited fewer spikes when surrounded by an adapting noise stimulus (Adapted condition), even when the amplitude of the adaptive noise stimulus was relatively small compared to the amplitude of the feature (shown for an example neuron in Figure 1B; AF = 8°, AN = 0.32°). In this example neuron, the Not Adapted feature response was strong (as defined by the number of elicited spikes) and temporally precise (as defined by the first spike latency jitter) on nearly every trial (Figure 1B; Not Adapted). In contrast, the Adapted neural response for this example neuron showed greater background firing due to the evoked response from the adapting stimulation and reduced feature-evoked activity (Figure 1B; Adapted). Across cells, the background firing activity due to the evoked response from the adapting stimulus was increased relative to the spontaneous firing in the Not Adapted condition (p = 1.18e-5, paired Wilcoxon signed-rank test, data not shown). The response to the stimulus feature (RF), defined as the number of spikes in a 10 millisecond window following feature presentation (see Supplemental Experimental Procedures), increased with increasing feature amplitude across cells (Figure 1C solid, Not Adapted; n = 26 cells), but was significantly attenuated in the Adapted condition (Figure 1C dashed, Adapted; n = 26 cells, *p
