Modeling and Analysis of Neural Spike Trains

open

Neuronal correlates of tactile working memory in rat barrel cortex and prefrontal cortex

The neuronal mechanisms of parametric working memory \u2013 the short-term storage of graded stimuli to guide behavior \u2013 are not fully elucidated. We have designed a working memory task where rats compare two sequential vibrations, S1 and S2, delivered to their whiskers (Fassihi et al, 2014). Vibrations are a series of velocities sampled from a zero-mean normal distribution. Rats must judge which stimulus had greater velocity standard deviation, \u3c3 (e.g. \u3c31 > \u3c32 turn left, \u3c31 < \u3c32 turn right). A critical operation in this task is to hold S1 information in working memory for subsequent comparison. In an earlier work we uncovered this cognitive capacity in rats (Fassihi et al, 2014), an ability previously ascribed only to primates. Where in the brain is such a memory kept and what is the nature of its representation? To address these questions, we performed simultaneous multi-electrode recordings from barrel cortex \u2013 the entryway of whisker sensory information into neocortex \u2013 and prelimbic area of medial prefrontal cortex (mPFC) which is involved in higher order cognitive functioning in rodents. During the presentation of S1 and S2, a majority of neurons in barrel cortex encoded the ongoing stimulus by monotonically modulating their firing rate as a function of \u3c3; i.e. 42% increased and 11% decreased their firing rate for progressively larger \u3c3 values. During the 2 second delay interval between the two stimuli, neuronal populations in barrel cortex kept a graded representation of S1 in their firing rate; 30% at early delay and 15% at the end. In mPFC, neurons expressed divers coding characteristics yet more than one-fourth of them varied their discharge rate according to the ongoing stimulus. Interestingly, a similar proportion carried the stimulus signal up to early parts of delay period. A smaller but considerable proportion (10%) kept the memory until the end of delay interval. We implemented novel information theoretic measures to quantify the stimulus and decision signals in neuronal responses in different stages of the task. By these measures, a decision signal was present in barrel cortex neurons during the S2 period and during the post stimulus delay, when the animal needed to postpone its action. Medial PFC units also represented animal choice, but later in the trial in comparison to barrel cortex. Decision signals started to build up in this area after the termination of S2. We implemented a regularized linear discriminant algorithm (RDA) to decode stimulus and decision signals in the population activity of barrel cortex and mPFC neurons. The RDA outperformed individual clusters and the standard linear discriminant analysis (LDA). The stimulus and animal\u2019s decision could be extracted from population activity simply by linearly weighting the responses of neuronal clusters. The population signal was present even in epochs of trial where no single cluster was informative. We predicted that coherent oscillations between brain areas might optimize the flow of information within the networks engaged by this task. Therefore, we quantified the phase synchronization of local field potentials in barrel cortex and mPFC. The two signals were coherent at theta range during S1 and S2 and, interestingly, prior to S1. We interpret the pre-stimulus coherence as reflecting top-down preparatory and expectation mechanisms. We showed, for the first time to our knowledge, the neuronal correlates of parametric working memory in rodents. The existence of both positive and negative codes in barrel cortex, besides the representation of stimulus memory and decision signals suggests that multiple functions might be folded into single modules. The mPFC also appears to be part of parametric working memory and decision making network in rats

A primate model of human cortical analysis of auditory objects

PhD ThesisThe anatomical organization of the auditory cortex in old world monkeys is similar to that in humans. But how good are monkeys as a model of human cortical analysis of auditory objects? To address this question I explore two aspects of auditory objectprocessing: segregation and timbre. Auditory segregation concerns the ability of animals to extract an auditory object of relevance from a background of competing sounds. Timbre is an aspect of object identity distinct from pitch. In this work, I study these phenomena in rhesus macaques using behaviour and functional magnetic resonance imaging (fMRI). I specifically manipulate one dimension of timbre, spectral flux: the rate of change of spectral energy.I present this thesis in five chapters. Chapter 1 presents background on auditory processing, macaque auditory cortex, models of auditory segregation, and dimensions of timbre. Chapter 2 presents an introduction to fMRI, the design of the fMRI experiments and analysis of fMRI data, and macaque behavioural training techniques employed. Chapter 3 presents results from the fMRI and behavioural experiments on macaques using a stochastic figure-ground stimulus. Chapter 4 presents the results from the fMRI experiment in macaques using spectral flux stimulus. Chapter 5 concludes with a general discussion of the results from both the studies and some future directions for research.In summary, I show that there is a functional homology between macaques and humans in the cortical processing of auditory figure-ground segregation. However, there is no clear functional homology in the processing of spectral flux between these species. So I conclude that, despite clear similarities in the organization of the auditory cortex and processing of auditory object segregation, there are important differences in how complex cues associated with auditory object identity are processed in the macaque and human auditory brains.Wellcome Trust U

Using auditory augmented reality to understand visual scenes

Locating objects in space is typically thought of as a visual task. However, not everyone has access to visual information, such as the blind. The purpose of this thesis was to investigate whether it was possible to convert visual events into spatial auditory cues. A neuromorphic retina was used to collect visual events and custom software was written to augment auditory localization cues into the scene. The neuromorphic retina is engineered to encode data similar to how the dorsal visual pathway does. The dorsal visual pathway is associated with fast nonredundant information encoding and is thought to drive attentional shifting, especially in the presence of visual transients. The intent was to create a device capable of using these visual onsets and transients to generate spatial auditory cues. To achieve this, the device uses the core principles driving auditory localization, with a focus on the interaural time and level difference cues. These cues are thought to be responsible for encoding azimuthal location in space. Results demonstrate the usefulness of such a device, but personalization will probably improve the effectiveness of the cues generated. In summary, I have created a device that converts purely visual events into useful auditory cues for localization, thereby granting perception of stimuli that may have been inaccessible to the user

Genetic dissection of circuits underlying the modular structure of the Superior Colliculus

In order to successfully interact with the environment, animals need to produce accurate movements towards specific positions in space. A crucial region of the brain that guides such goal-oriented movements is the superior colliculus (SC), an evolutionary conserved structure of the midbrain. While several lines of research in different model organisms have confirmed that the SC contributes to the initiation of orienting movements, how functionally distinct neuronal groups within the SC are organized to support the production of such motor outputs is poorly understood. One of the reasons why the intrinsic circuit organization of the SC remains elusive is the lack of genetic characterization of the neuronal populations of the motor SC. Here, we performed RNAseq to screen for genetic markers for neuronal subpopulations in the motor SC. We identified a transcription factor, Pitx2, which is exclusively expressed in a subpopulation of glutamatergic neurons in the motor domain of the SC. Strikingly, this population of neurons displays a non-homogenous distribution within the motor layer of the SC, being organised in clusters along the mediolateral and anteroposterior axis. We mapped the pre-synaptic network and the post-synaptic targets of Pitx2ON neurons, unveiling that this modular population receives direct inputs from motor and sensory cortical regions, as well as several midbrain nuclei involved in movement control, and sends projection along the cephalomotor pathway. We then asked whether these modules may act as functional units, each integrating multimodal sensory information and encoding a specific feature of head movement, the main ethologically relevant orienting behaviour in rodents. Optogenetic activation of this modular population in freely moving animals produced a stereotyped, robust head motion characterised by a pronounced quantal nature; furthermore, the amplitude of the elicited head movement varied based on the modular unit activated. Our results suggest that distinct clusters of genetically defined neurons produce head displacement along a characteristic vector. In conclusion, we found that a population of premotor neurons in the SC is organised in a modular conformation and we suggest that such modularity may represent a physical implementation of a discontinuous motor map for orienting movements encoded in the mouse SC. Our work complements previous observations of periodicity in SC circuitry, as well as its afferent and efferent systems. Exploiting the genetic toolkit available in the mouse, our work begins to address the functional relevance of this modularity and paves the way for future experiments to investigate principles of sensorimotor integration in SC circuits.MR

Neural mechanisms of auditory scene analysis in a non-mammalian animal model

University of Minnesota Ph.D. dissertation. September 2014. Major: Neuroscience. Advisor: Mark A. Bee. 1 computer file (PDF); iv, 178 pages, appendices 1-2.Healthy auditory systems perform well in quiet places where there are no overlapping sounds, but are greatly challenged in noisy environments. In these environments, all of the sounds in the "acoustic scene" combine to create a single waveform that impinges on the receiver's ear, from which the auditory system must extract some meaningful signal. A particular example of this auditory scene analysis occurs in multi-talker environments, where the acoustic scene consists of the overlapping sounds of competing signalers. The problem of communicating in multi-talker environments has been well-studied in the human hearing literature, where it is known as the cocktail party problem, but it is not unique to humans. Many non-human animals also encounter noisy social environments and have evolved to solve cocktail-party-like problems of vocal communication. However, the mechanisms that humans and other animals use to solve the problem may differ. While human and other vertebrate auditory systems share ancestral traits from their most recent common ancestor, there is evidence for divergence of auditory systems between the separate tetrapod lineages. The independent evolution of auditory systems suggests that vertebrates may have evolved ta diversity of novel solutions to cocktail-party-like problems. Traditionally, research into similar problems in other non-human animals has been limited. The aim of my dissertation research was to investigate mechanisms that enable a non-mammalian vertebrate, specifically a frog, to navigate noisy, multi-signaler environments

Neural Models of Subcortical Auditory Processing

An important feature of the auditory system is its ability to distinguish many simultaneous sound sources. The primary goal of this work was to understand how a robust, preattentive analysis of the auditory scene is accomplished by the subcortical auditory system. Reasonably accurate modelling of the morphology and organisation of the relevant auditory nuclei, was seen as being of great importance. The formulation of plausible models and their subsequent simulation was found to be invaluable in elucidating biological processes and in highlighting areas of uncertainty. In the thesis, a review of important aspects of mammalian auditory processing is presented and used as a basis for the subsequent modelling work. For each aspect of auditory processing modelled, psychophysical results are described and existing models reviewed, before the models used here are described and simulated. Auditory processes which are modelled include the peripheral system, and the production of tonotopic maps of the spectral content of complex acoustic stimuli, and of modulation frequency or periodicity. A model of the formation of sequential associations between successive sounds is described, and the model is shown to be capable of emulating a wide range of psychophysical behaviour. The grouping of related spectral components and the development of pitch perception is also investigated. Finally a critical assessment of the work and ideas for future developments are presented. The principal contributions of this work are the further development of a model for pitch perception and the development of a novel architecture for the sequential association of those groups. In the process of developing these ideas, further insights into subcortical auditory processing were gained, and explanations for a number of puzzling psychophysical characteristics suggested.Royal Naval Engineering College, Manadon, Plymout

Avian Sleep Homeostasis: Electrophysiological, Molecular and Evolutionary Approaches

The function of slow wave sleep (SWS) and rapid eye movement (REM) sleep in mammals is an unanswered question in neuroscience. Aside from mammals, only birds engage in these states. Because birds independently evolved SWS and REM sleep, the study of sleeping birds may help identify shared traits related to the function of these states. Throughout this dissertation, we apply such a bird’s perspective to the sleeping brain. We begin with a review on knowledge gained through the study of sleep in animals (Chapter 1). Next, we present results from the first electrophysiological study of sleep in the most basal group of living birds by studying ostriches (Chapter 2). Although ostriches engage in unequivocal SWS, their REM sleep electrophysiology is unique and resembles features of REM sleep present only in basal mammals. Thus, the evolution REM sleep may have followed a recurring sequence of steps in mammals and birds. The remaining chapters deal with the regulation of sleep (or sleep homeostasis). Sleep homeostasis refers to an increase in the intensity of sleep (typically quantified as slow wave activity, SWA) following an extended period of wakefulness. Although such a response has long been known to occur in mammals, it has been unclear whether birds are capable of similar changes in SWA following sleep loss. We provide the first experimental evidence for a mammalian-like increase in SWA following enforced wakefulness in birds (Chapter 3). In mammals, SWA increases locally in brain regions used more during prior wakefulness. To see if SWS is regulated locally in birds, we stimulated one part of the pigeon brain during enforced wakefulness and observed a local increase in SWA during subsequent sleep (Chapter 4). Brain regions not stimulated asymmetrically during wakefulness showed a symmetric increase in SWA. These patterns of a/symmetry may reflect changes in the strength of synapses, as they do in mammals, because they are mirrored by changes in the slope of slow waves during SWS – a purported marker of synaptic strength. Lastly, we investigate whether local increases in SWA in birds are mediated by similar molecular mechanisms to those of mammals (Chapter 5). Surprisingly, mRNA levels of such proteins did not respond to unilateral visual stimulation during enforced wakefulness in the manner predicted based on work derived from mammals, but further study is needed to resolve the meaning of this difference. Overall, this dissertation presents several novel findings on the evolution and regulation of avian sleep

Sound processing in the mouse auditory cortex: organization, modulation, and transformation

The auditory system begins with the cochlea, a frequency analyzer and signal amplifier with exquisite precision. As neural information travels towards higher brain regions, the encoding becomes less faithful to the sound waveform itself and more influenced by non-sensory factors such as top-down attentional modulation, local feedback modulation, and long-term changes caused by experience. At the level of auditory cortex (ACtx), such influences exhibit at multiple scales from single neurons to cortical columns to topographic maps, and are known to be linked with critical processes such as auditory perception, learning, and memory. How the ACtx integrates a wealth of diverse inputs while supporting adaptive and reliable sound representations is an important unsolved question in auditory neuroscience. This dissertation tackles this question using the mouse as an animal model. We begin by describing a detailed functional map of receptive fields within the mouse ACtx. Focusing on the frequency tuning properties, we demonstrated a robust tonotopic organization in the core ACtx fields (A1 and AAF) across cortical layers, neural signal types, and anesthetic states, confirming the columnar organization of basic sound processing in ACtx. We then studied the bottom-up input to ACtx columns by optogenetically activating the inferior colliculus (IC), and observed feedforward neuronal activity in the frequency-matched column, which also induced clear auditory percepts in behaving mice. Next, we used optogenetics to study layer 6 corticothalamic neurons (L6CT) that project heavily to the thalamus and upper layers of ACtx. We found that L6CT activation biases sound perception towards either enhanced detection or discrimination depending on its relative timing with respect to the sound, a process that may support dynamic filtering of auditory information. Finally, we optogenetically isolated cholinergic neurons in the basal forebrain (BF) that project to ACtx and studied their involvement in columnar ACtx plasticity during associative learning. In contrast to previous notions that BF just encodes reward and punishment, we observed clear auditory responses from the cholinergic neurons, which exhibited rapid learning-induced plasticity, suggesting that BF may provide a key instructive signal to drive adaptive plasticity in ACtx