Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Change blindness: eradication of gestalt strategies

Arrays of eight, texture-defined rectangles were used as stimuli in a one-shot change blindness (CB) task where there was a 50% chance that one rectangle would change orientation between two successive presentations separated by an interval. CB was eliminated by cueing the target rectangle in the first stimulus, reduced by cueing in the interval and unaffected by cueing in the second presentation. This supports the idea that a representation was formed that persisted through the interval before being 'overwritten' by the second presentation (Landman et al, 2003 Vision Research 43149–164]. Another possibility is that participants used some kind of grouping or Gestalt strategy. To test this we changed the spatial position of the rectangles in the second presentation by shifting them along imaginary spokes (by ±1 degree) emanating from the central fixation point. There was no significant difference seen in performance between this and the standard task [F(1,4)=2.565, p=0.185]. This may suggest two things: (i) Gestalt grouping is not used as a strategy in these tasks, and (ii) it gives further weight to the argument that objects may be stored and retrieved from a pre-attentional store during this task

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

Towards building a more complex view of the lateral geniculate nucleus: Recent advances in understanding its role

The lateral geniculate nucleus (LGN) has often been treated in the past as a linear filter that adds little to retinal processing of visual inputs. Here we review anatomical, neurophysiological, brain imaging, and modeling studies that have in recent years built up a much more complex view of LGN . These include effects related to nonlinear dendritic processing, cortical feedback, synchrony and oscillations across LGN populations, as well as involvement of LGN in higher level cognitive processing. Although recent studies have provided valuable insights into early visual processing including the role of LGN, a unified model of LGN responses to real-world objects has not yet been developed. In the light of recent data, we suggest that the role of LGN deserves more careful consideration in developing models of high-level visual processing

Fractals in the Nervous System: conceptual Implications for Theoretical Neuroscience

This essay is presented with two principal objectives in mind: first, to document the prevalence of fractals at all levels of the nervous system, giving credence to the notion of their functional relevance; and second, to draw attention to the as yet still unresolved issues of the detailed relationships among power law scaling, self-similarity, and self-organized criticality. As regards criticality, I will document that it has become a pivotal reference point in Neurodynamics. Furthermore, I will emphasize the not yet fully appreciated significance of allometric control processes. For dynamic fractals, I will assemble reasons for attributing to them the capacity to adapt task execution to contextual changes across a range of scales. The final Section consists of general reflections on the implications of the reviewed data, and identifies what appear to be issues of fundamental importance for future research in the rapidly evolving topic of this review

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

Models of spatial representation in the medial entorhinal cortex

Komplexe kognitive Funktionen wie Gedächtnisbildung, Navigation und Entscheidungsprozesse hängen von der Kommunikation zwischen Hippocampus und Neokortex ab. An der Schnittstelle dieser beiden Gehirnregionen liegt der entorhinale Kortex - ein Areal, das Neurone mit bemerkenswerten räumlichen Repräsentationen enthält: Gitterzellen. Gitterzellen sind Neurone, die abhängig von der Position eines Tieres in seiner Umgebung feuern und deren Feuerfelder ein dreieckiges Muster bilden. Man vermutet, dass Gitterzellen Navigation und räumliches Gedächtnis unterstützen, aber die Mechanismen, die diese Muster erzeugen, sind noch immer unbekannt. In dieser Dissertation untersuche ich mathematische Modelle neuronaler Schaltkreise, um die Entstehung, Weitervererbung und Verstärkung von Gitterzellaktivität zu erklären. Zuerst konzentriere ich mich auf die Entstehung von Gittermustern. Ich folge der Idee, dass periodische Repräsentationen des Raumes durch Konkurrenz zwischen dauerhaft aktiven, räumlichen Inputs und der Tendenz eines Neurons, durchgängiges Feuern zu vermeiden, entstehen könnten. Aufbauend auf vorangegangenen theoretischen Arbeiten stelle ich ein Einzelzell-Modell vor, das gitterartige Aktivität allein durch räumlich-irreguläre Inputs, Feuerratenadaptation und Hebbsche synaptische Plastizität erzeugt. Im zweiten Teil der Dissertation untersuche ich den Einfluss von Netzwerkdynamik auf das Gitter-Tuning. Ich zeige, dass Gittermuster zwischen neuronalen Populationen weitervererbt werden können und dass sowohl vorwärts gerichtete als auch rekurrente Verbindungen die Regelmäßigkeit von räumlichen Feuermustern verbessern können. Schließlich zeige ich, dass eine entsprechende Konnektivität, die diese Funktionen unterstützt, auf unüberwachte Weise entstehen könnte. Insgesamt trägt diese Arbeit zu einem besseren Verständnis der Prinzipien der neuronalen Repräsentation des Raumes im medialen entorhinalen Kortex bei.High-level cognitive abilities such as memory, navigation, and decision making rely on the communication between the hippocampal formation and the neocortex. At the interface between these two brain regions is the entorhinal cortex, a multimodal association area where neurons with remarkable representations of self-location have been discovered: the grid cells. Grid cells are neurons that fire according to the position of an animal in its environment and whose firing fields form a periodic triangular pattern. Grid cells are thought to support animal's navigation and spatial memory, but the cellular mechanisms that generate their tuning are still unknown. In this thesis, I study computational models of neural circuits to explain the emergence, inheritance, and amplification of grid-cell activity. In the first part of the thesis, I focus on the initial formation of grid-cell tuning. I embrace the idea that periodic representations of space could emerge via a competition between persistently-active spatial inputs and the reluctance of a neuron to fire for long stretches of time. Building upon previous theoretical work, I propose a single-cell model that generates grid-like activity solely form spatially-irregular inputs, spike-rate adaptation, and Hebbian synaptic plasticity. In the second part of the thesis, I study the inheritance and amplification of grid-cell activity. Motivated by the architecture of entorhinal microcircuits, I investigate how feed-forward and recurrent connections affect grid-cell tuning. I show that grids can be inherited across neuronal populations, and that both feed-forward and recurrent connections can improve the regularity of spatial firing. Finally, I show that a connectivity supporting these functions could self-organize in an unsupervised manner. Altogether, this thesis contributes to a better understanding of the principles governing the neuronal representation of space in the medial entorhinal cortex

Treatise on Hearing: The Temporal Auditory Imaging Theory Inspired by Optics and Communication

A new theory of mammalian hearing is presented, which accounts for the auditory image in the midbrain (inferior colliculus) of objects in the acoustical environment of the listener. It is shown that the ear is a temporal imaging system that comprises three transformations of the envelope functions: cochlear group-delay dispersion, cochlear time lensing, and neural group-delay dispersion. These elements are analogous to the optical transformations in vision of diffraction between the object and the eye, spatial lensing by the lens, and second diffraction between the lens and the retina. Unlike the eye, it is established that the human auditory system is naturally defocused, so that coherent stimuli do not react to the defocus, whereas completely incoherent stimuli are impacted by it and may be blurred by design. It is argued that the auditory system can use this differential focusing to enhance or degrade the images of real-world acoustical objects that are partially coherent. The theory is founded on coherence and temporal imaging theories that were adopted from optics. In addition to the imaging transformations, the corresponding inverse-domain modulation transfer functions are derived and interpreted with consideration to the nonuniform neural sampling operation of the auditory nerve. These ideas are used to rigorously initiate the concepts of sharpness and blur in auditory imaging, auditory aberrations, and auditory depth of field. In parallel, ideas from communication theory are used to show that the organ of Corti functions as a multichannel phase-locked loop (PLL) that constitutes the point of entry for auditory phase locking and hence conserves the signal coherence. It provides an anchor for a dual coherent and noncoherent auditory detection in the auditory brain that culminates in auditory accommodation. Implications on hearing impairments are discussed as well.Comment: 603 pages, 131 figures, 13 tables, 1570 reference