Effects of Adaptation on Discrimination of Whisker Deflection Velocity and Angular Direction in a Model of the Barrel Cortex

Two important stimulus features represented within the rodent barrel cortex are velocity and angular direction of whisker deflection. Each cortical barrel receives information from thalamocortical (TC) cells that relay information from a single whisker, and TC input is decoded by barrel regular-spiking (RS) cells through a feedforward inhibitory architecture (with inhibition delivered by cortical fast-spiking or FS cells). TC cells encode deflection velocity through population synchrony, while deflection direction is encoded through the distribution of spike counts across the TC population. Barrel RS cells encode both deflection direction and velocity with spike rate, and are divided into functional domains by direction preference. Following repetitive whisker stimulation, system adaptation causes a weakening of synaptic inputs to RS cells and diminishes RS cell spike responses, though evidence suggests that stimulus discrimination may improve following adaptation. In this work, I construct a model of the TC, FS, and RS cells comprising a single barrel system the model incorporates realistic synaptic connectivity and dynamics and simulates both angular direction (through the spatial pattern of |C activation) and velocity (through synchrony of the TC population spikes) of a deflection of the primary whisker, and I use the model to examine direction and velocity selectivity of barrel RS cells before and after adaptation. I find that velocity and direction selectivity of individual RS cells (measured over multiple trials) sharpens following adaptation, but stimulus discrimination using a simple linear classifier by the RS population response during a single trial (a more biologically meaningful measure than single cell discrimination over multiple trials) exhibits strikingly different behavior velocity discrimination is similar both before and after adaptation, while direction classification improves substantially following adaptation. This is the first model, to my knowledge, that simulates both whisker deflection velocity and angular direction and examines the ability of the RS population response to pinpoint both stimulus features within the context of adaptation

Sensory coding in supragranular cells of the vibrissal cortex in anesthetized and awake mice

Sensory perception entails reliable representation of the external stimuli as impulse activity of individual neurons (i.e. spikes) and neuronal populations in the sensory area. An ongoing challenge in neuroscience is to identify and characterize the features of the stimuli which are relevant to a specific sensory modality and neuronal strategies to effectively and efficiently encode those features. It is widely hypothesized that the neuronal populations employ “sparse coding” strategies to optimize the stimulus representations with a low energetic cost (i.e. low impulse activity). In the past two decades, a wealth of experimental evidence has supported this hypothesis by showing spatiotemporally sparse activity in sensory area. Despite numerous studies, the extent of sparse coding and its underlying mechanisms are not fully understood, especially in primary vibrissal somatosensory cortex (vS1), which is a key model system in sensory neuroscience. Importantly, it is not clear yet whether sparse activation of supragranular vS1 is due to insufficient synaptic input to the majority of the cells or the absence of effective stimulus features. In this thesis, first we asked how the choice of stimulus could affect the degree of sparseness and/or the overall fraction of the responsive vS1 neurons. We presented whisker deflections spanning a broad range of intensities, including “standard stimuli” and a high-velocity, “sharp” stimulus, which simulated the fast slip events that occur during whisker mediated object palpation. We used whole-cell and cell-attached recording and calcium imaging to characterize the neuronal responses to these stimuli. Consistent with previous literature, whole-cell recording revealed a sparse response to the standard range of velocities: although all recorded cells showed tuning to velocity in their postsynaptic potentials, only a small fraction produced stimulus-evoked spikes. In contrast, the sharp stimulus evoked reliable spiking in a large fraction of regular spiking neurons in the supragranular vS1. Spiking responses to the sharp stimulus were binary and precisely timed, with minimum trial-to-trial variability. Interestingly, we also observed that the sharp stimulus produced a consistent and significant reduction in action potential threshold. In the second step we asked whether the stimulus dependent sparse and dense activations we found in anesthetized condition would generalize to the awake condition. We employed cell-attached recordings in head-fixed awake mice to explore the degree of sparseness in awake cortex. Although, stimuli delivered by a piezo-electric actuator evoked significant response in a small fraction of regular spiking supragranular neurons (16%-29%), we observed that a majority of neurons (84%) were driven by manual probing of whiskers. Our results demonstrate that despite sparse activity, the majority of neurons in the superficial layers of vS1 contribute to coding by representing a specific feature of the tactile stimulus. Thesis outline: Chapter 1 provides a review of the current knowledge on sparse coding and an overview of the whisker-sensory pathway. Chapter 2 represents our published results regarding sparse and dense coding in vS1 of anesthetized mice (Ranjbar-Slamloo and Arabzadeh 2017). Chapter 3 represents our pending manuscript with results obtained with piezo and manual stimulation in awake mice. Finally, in Chapter 4 we discuss and conclude our findings in the context of the literature. The appendix provides unpublished results related to Chapter 2. This section is referenced in the final chapter for further discussion

Disentanglement of Whisker Deflection Velocity and Direction

The easily identifiable structure and clearly defined function of the rodent somatosensory barrel cortex has made it a model system for study in neuroscience. The barrel consists of ~3600 regular-spiking (RS) cells that receive inhibitory inputs from(FS) cells, both of which are excited by ~240 thalamocortical (TC) cells. RS cell population dynamics such as rate of spiking and region of increased spiking can encode velocity and directional information from the initial whisker deflection, however, behavior of any single RS cell (or small group of RS cells) may be ambiguously affected by both velocity and directional changes. This project set out to create an additional layer of RS-like cells, hereby referred to as “excitatory extensions,” whose individual behavior or small group dynamics can correctly classify velocity and directional information from the incoming input stimulus. The model shows that an architecture that takes advantage of the net scaling of RS cell layer activity can lead to EE cells that correctly classify velocity without dependency on directional input. The model also shows that an architecture that engages an inhibitory feedback system can lead to EE cells that correctly classify direction without dependency on velocity input. Further areas of study include putting two barrel systems in communication with one another while limiting the model to experimentally-supported cell dynamics to see if architecture similar to the ones discovered in this project arise

Effects of Adaptation in a Somatosensory Thalamocortical Circuit

In the mammalian brain, thalamocortical circuits perform the initial stage of processing before information is sent to higher levels of the cerebral cortex. Substantial changes in receptive field properties are produced in the thalamocortical response transformation. In the whisker-to-barrel thalamocortical pathway, the response magnitude of barrel excitatory cells is sensitive to the velocity of whisker deflections, whereas in the thalamus, velocity is only encoded by firing synchrony. The behavior of this circuit can be captured in a model which contains a window of opportunity for thalamic firing synchrony to engage intra-barrel recurrent excitation before being 'damped' by slightly delayed, but strong, local feedforward inhibition. Some remaining aspects of the model that require investigation are: (1) how does adaptation with ongoing and repetitive sensory stimulation affect processing in this circuit and (2) what are the rules governing intra-barrel interactions. By examining sensory processing in thalamic barreloids and cortical barrels, before and after adaptation with repetitive high-frequency whisker stimulation, I have determined that adaptation modifies the operations of the thalamocortical circuit without fundamentally changing it. In the non-adapted state, higher velocities produce larger responses in barrel cells than lower velocities. Similarly, in the adapted barrel, putative excitatory and inhibitory neurons can respond with temporal fidelity to high-frequency whisker deflections if they are of sufficient velocity. Additionally, before and after adaptation, relative to putative excitatory cells, inhibitory cells produce larger responses and are more broadly-tuned for stimulus parameters (e.g., the angle of whisker deflection). In barrel excitatory cells, adaptation is angularly-nonspecific; that is, response suppression is not specific to the angle of the adapting stimulus. The angular tuning of barrel excitatory cells is sharpened and the original angular preference is maintained. This is consistent with intra-barrel interactions being angularly-nonspecific. The maintenance of the original angular preference also suggests that the same thalamocortical inputs determine angular tuning before and after adaptation. In summary, the present findings suggest that adaptation narrows the window of opportunity for synchronous thalamic inputs to engage recurrent excitation so that it can withstand strong, local inhibition. These results from the whisker-to-barrel thalamocortical response transformation are likely to have parallels in other systems

In vivo Dissection of Long Range Inputs to the Rat Barrel Cortex

Layer 1 (L1) of the cerebral cortex is a largely acellular layer that consists mainly of long-range projection axons and apical dendrites of deeper pyramidal neurons. In the rodent barrel cortex, L1 contains axons from both higher motor and sensory areas of the brain. Despite the abundance of synapses in L1 their actual contribution to sensory processing remains unknown. We investigated the impact of activating long-range axons on barrel cortex L2/3 pyramidal neurons in vivo using a combination of optogenetics and eletrophysiological techniques. The reason we target our investigation on L2/3 is because of its well-known sparse sensory responses. We hypothesize that long-range top-down inputs via L1 can provide the additional inputs necessary to unleash L2/3 and strongly influence sensory processing in S1. We focused on three main sources of BC-projecting synapses: the posterior medial nucleus of the thalamus (POm, the secondary somatosensory nucleus), the primary motor cortex (M1), and the secondary somatosensory cortex (S2). Here we report that while activation of POm axons elicits strong EPSPs in most recorded L2/3 cells, activation of M1 or S2 axons elicited small or no detectable responses. Only POm activation boosted sensory responses in L2/3 pyramidal neurons. We also found that during wakefulness and under sedation, POM activation not only elicited a strong fast-onset EPSP in L2/3 neurons, but also a delayed persistent response. Pharmacological inactivation of POM abolished this persistent response but not the initial synaptic volley to L2/3. We conclude that the persistent response requires intrathalamic or thalamocortical circuits and cannot be mediated by specialized synaptic terminals or intracortical circuitry. Overall, our study suggests that the higher order thalamic nucleus provides more powerful network effect on L2/3 sensory processing than higher order cortical feedback inputs. POm activation not only directly boosts L2/3 sensory responses, but is also capable of influencing S1 signal processing for prolonged periods of time after stimulus onset and can potentially be important for other cognitive aspects of sensory computation

Two-photon all-optical interrogation of mouse barrel cortex during sensory discrimination

The neocortex supports a rich repertoire of cognitive and behavioural functions, yet the rules, or neural ‘codes’, that determine how patterns of cortical activity drive perceptual processes remain enigmatic. Experimental neuroscientists study these codes through measuring and manipulating neuronal activity in awake behaving subjects, which allows links to be identified between patterns of neural activity and ongoing behaviour functions. In this thesis, I detail the application of novel optical techniques for simultaneously recording and manipulating neurons with cellular resolution to examine how tactile signals are processed in sparse neuronal ensembles in mouse somatosensory ‘barrel’ cortex. To do this, I designed a whisker-based perceptual decision-making task for head-fixed mice, that allows precise control over sensory input and interpretable readout of perceptual choice. Through several complementary experimental approaches, I show that task performance is exquisitely coupled to barrel cortical activity. Using two- photon calcium imaging to simultaneously record from populations of barrel cortex neurons, I demonstrate that different subpopulations of neurons in layer 2/3 (L2/3) show selectivity for contralateral and ipsilateral whisker input during behaviour. To directly test whether these stimulus-tuned groups of neurons differentially impact perceptual decision-making I performed patterned photostimulation experiments to selectively activate these functionally defined sets of neurons and assessed the resulting impact on behaviour and the local cortical network in layer 2/3. In contrast with the expected results, stimulation of sensory-coding neurons appeared to have little perceptual impact on task performance. However, activation of non- stimulus coding neurons did drive decision biases. These results challenge the conventional view that strongly sensory responsive neurons carry more perceptual weight than non-responsive sensory neurons during perceptual decision-making. Furthermore, patterned photostimulation revealed and imposed potent surround suppression in L2/3, which points to strong lateral inhibition playing a dominant role in shaping spatiotemporally sparse activity patterns. These results showcase the utility of combined patterned photostimulation methods and population calcium imaging for revealing and testing neural circuit function during sensorimotor behaviour and provide new perspectives on sensory coding in barrel cortex

The Timescales of Transformation Across Brain Structures in the Thalamocortical Circuit

Sensory processing requires reliable transmission of sensory information across multiple brain regions, from peripheral sensors, through sub-cortical structures, to sensory cortex, ultimately producing the sensory representations that drive perception and behavior. Despite decades of research, we do not yet have a mechanistic understanding of how neural representations are transformed across these critical brain structures. This is primarily due to the fact that what we know at the circuit level has been mainly derived from electrophysiological recordings targeted at single regions and upon gross anatomical connection patterns across brain regions without specific, precise knowledge of synaptic connectivity. To fill this gap in knowledge and to uncover how signaling changes across brain regions in response to changes in the sensory environment, this thesis work has two primary contributions. First, we developed a work-flow of topographic mapping and histological validation for extracellular multi-electrode recordings of neurons in the thalamocortical circuit in rodents, followed by a novel statistical approach for inferring synaptic connectivity across the brain regions. Specifically, we developed a signal-detection based classification of synaptic connectivity in the thalamus and S1 cortex, with an assessment of classification confidence that is scalable to the large-scale recording approaches that are emerging in the field. Utilizing this experimental and computational framework, we next investigated the neural mechanisms that underlie an important sensory phenomenon that emerges in this early sensory circuit: rapid sensory adaptation. While this phenomenon has been well-studied over very rapid timescales of hundreds of milliseconds, other studies suggest that longer time scales of 10’s of seconds may also be relevant. Here, we demonstrated that the thalamus and the thalamorecipient layer 4 excitatory and inhibitory neurons in S1 exhibit differential adaptation dynamics, and that the neuronal dynamics across these different regions and cell types show common signatures of multiple timescales in response to sensory adaptation. We characterized the adaptation profiles at the TC junction and further identified several mechanisms that potentially underlie the adaptation effects on the circuit dynamics, including synaptic depression of the TC synapse in identified monosynaptically connected thalamic and cortical neurons, and changes in spike timing and synchronization in the thalamic population. These mechanisms together mediate a dynamic trade-off in the theoretical detectability and discriminability of stimulus inputs. These results suggest that adaptation of the thalamocortical circuit across timescales results from a complex interaction between distinct mechanisms, and notably the engagement of different mechanisms can shift depending on the timescale of environmental changes.Ph.D

MOTOR CORTEX REGULATION OF THALAMIC-CORTICAL ACTIVITY IN THE SOMATOSENSORY SYSTEM

A prominent feature of thalamocortical circuitry in sensory systems is the extensive and highly organized feedback projection from the cortex to thalamic neurons that provide input to it. Intriguingly, many corticothalamic (CT) neurons are weakly responsive to peripheral stimuli, or silent altogether. Here using the whisker-to-barrel system, we examine whether the responses of CT neurons and their related thalamic neurons are affected by motor cortex, a prominent source of input to deep layers of the somatosensory cortex. Pharmacological facilitation of motor cortex activity produced using focal, microiontophoresis leads to enhanced whisker-evoked firing of topographically aligned layer 6 neurons, including identified CT cells, and of cells in corresponding regions of the thalamic ventral posterior medial nucleus (VPm barreloids). Together, the findings raise the possibility that cortico-thalamo-cortical circuitry in primary sensory areas is engaged by other functionally related cortical centers, providing a means for context-dependent regulation of information processing within thalamocortical circuits.We investigated how vMCx influence activity in thalamic VPm nucleus in a freely behaving rat. We examine afferent-evoked thalamic activity in animals that are either alert but voluntarily relatively motionless or actively whisking in the air without object contact. Afferent activity is evoked in VPm by means of electrical microstimulation of a single whisker follicle. In some experiments, neural processing in brainstem trigeminal nuclei was either by-passed by means of medial lemniscus stimulation, or altered by pharmacological intervention. We found that sensory responses during voluntary whisker movements, when motor cortex is likely to be active, are reduced relative to responses that occur during periods of wakeful quiescence. Enhancement of thalamic activity during whisking can be observed, however, when signal processing in sub-thalamic centers is either by-passed or experimentally altered. Findings suggest that during voluntary movement activity within the lemniscal system is globally diminished, perhaps at early, brainstem levels at the same time that activity within specific thalamocortical neuronal populations is facilitated. Though activity levels are reduced system-wide, activity within some local circuits may be subject to less net suppression. This decrease in suppression may occur on a moment-to-moment basis in a context-dependent manner. Thus, during voluntary whisker movement, sensory transmission in thalamocortical circuits may be modulated according to specific activation patterns distributed across the motor map