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

Mechanisms Underlying Maintenance of Adult Visual Receptive Fields

The establishment of neuronal connections requires a sequence of orchestrated events including neuronal migration, axon guidance, synapse formation and elimination, and circuit fine-tuning. Understanding the molecular signaling pathways that underlie these processes is fundamental to understanding how the nervous system is assembled and how it functions. In this dissertation, I investigated the molecular mechanisms mediating the effects of visual experience in the development and plasticity of the visual pathway. Each neuron receiving visual input responds to a specific area of the visual field- their receptive field (RF). During early development RFs refine in size, an important property of visual acuity. Utilizing the sensory deprivation model of dark rearing (DR) in Syrian hamsters (Mesocricerus auratus), I investigated the signaling mechanisms underlying RF refinement and plasticity. Our lab has previously reported that the developmental refinement of RFs happens independently of visual experience in both superior colliculus (SC) and visual cortex (V1), but fails to be maintained without sufficient visual experience during an early critical period (CP). Using a pharmacological approach, I show that BDNF/TrkB signaling is crucial for the maintenance of RF refinement in SC. DR hamsters treated with a TrkB agonist during the CP for RF refinement maintenance (P33-P40) have mature RFs in adulthood. Hamsters given visual experience, but treated with a TrkB antagonist during the CP have enlarged (unrefined) RFs in adulthood. I also show that refined RFs are essential for enhancing both looming escape behaviors, and spatial discrimination of sinusoidal gratings. How early visual experience prevents plasticity in adulthood (resulting in a loss of RF maintenance) is poorly understood, but reduced GABAergic inhibition is involved. Using a molecular approach I identified several possible mechanisms mediating a loss of inhibition in SC of DR adults. Ultimately it appears that reduced expression of the GABA neurotransmitter is primarily responsible for loss of RF maintenance, rather than any post synaptic modifications. This work provides insight into the mechanisms of development and plasticity in the nervous system and could instruct therapies to prevent maladaptive plasticity in disease and to enhance recovery of function in adults

Microcircuit remodeling processes underlying learning in the adult

One of the most intriguing discoveries in neuroscience of the past decades has been showing that experience is able to induce structural modifications in cortical microcircuit that might underlie the formation of memories upon learning (for a review, see Caroni, Donato and Muller 2012). Hence, learning induces phases of synapse formation and elimination that are strictly regulated by a variety of mechanisms, which impact on cortical microcircuits affecting both excitatory and inhibitory neurons. Nevertheless, the extent to which specific configurations might be implemented to support specific phases of learning, as well as the impact of experience-induced structural modifications on further learning, is still largely unknown. Here, I explore how the remodeling of identified microcircuits in the mouse hippocampus and neocortex supports learning in the adult. In the first part, I identifiy a microcircuit module engaging VIP and Parvalbumin (PV) positive interneurons to regulate the state of the PV+ network upon experience. This defines states of enhanced or reduced structural plasticity and learning based on the distribution of PV intensity in the network. In the second part, I demonstrate how specific hippocampal subdivisions are exploited to learn subtasks of trial-and-errors forms of learning via the deployment of increasingly precise searching strategies, and sequential recruitment of ventral, intermediate, and dorsal hippocampus. In the third part, I highlight the existence of genetically matched subpopulations of principal cells in the hippocampus, which achieve selective connectivity across hippocampal subdivisions via matched windows of neurogenesis and synaptogenesis during development. In the fourth part, I investigate the maturation of microcircuits mediating feedforward inhibition in the hippocampus, and highlight windows during development for the establishment of the proper baseline configuration in the adult. Moreover, I identify a critical window for cognitive enhancement during hippocampal development. In the fifth part, I study how ageing affects the PV network in hippocampal CA3, providing evidence for which age related neuronal loss correlates to reduced incidental learning performances in old mice. Therefore, by manipulating the PV network early during life, I provide strategies to modulate cognitive decline

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

Visual Cortex

The neurosciences have experienced tremendous and wonderful progress in many areas, and the spectrum encompassing the neurosciences is expansive. Suffice it to mention a few classical fields: electrophysiology, genetics, physics, computer sciences, and more recently, social and marketing neurosciences. Of course, this large growth resulted in the production of many books. Perhaps the visual system and the visual cortex were in the vanguard because most animals do not produce their own light and offer thus the invaluable advantage of allowing investigators to conduct experiments in full control of the stimulus. In addition, the fascinating evolution of scientific techniques, the immense productivity of recent research, and the ensuing literature make it virtually impossible to publish in a single volume all worthwhile work accomplished throughout the scientific world. The days when a single individual, as Diderot, could undertake the production of an encyclopedia are gone forever. Indeed most approaches to studying the nervous system are valid and neuroscientists produce an almost astronomical number of interesting data accompanied by extremely worthy hypotheses which in turn generate new ventures in search of brain functions. Yet, it is fully justified to make an encore and to publish a book dedicated to visual cortex and beyond. Many reasons validate a book assembling chapters written by active researchers. Each has the opportunity to bind together data and explore original ideas whose fate will not fall into the hands of uncompromising reviewers of traditional journals. This book focuses on the cerebral cortex with a large emphasis on vision. Yet it offers the reader diverse approaches employed to investigate the brain, for instance, computer simulation, cellular responses, or rivalry between various targets and goal directed actions. This volume thus covers a large spectrum of research even though it is impossible to include all topics in the extremely diverse field of neurosciences

How aging shapes neural representations of continuous spaces

The human brain undergoes remarkable changes over the lifespan, including its structural as well as functional characteristics. One functional change that has been identified in the brain of older adults is the phenomenon of neural dedifferentiation. This describes a process in which neural responses lose specificity over the course of aging, rendering neural representations of, for instance, distinct visual categories increasingly similar to each other. Findings in non-human animals have shown that tuning profiles of neural populations over a continuous stimulus space (e.g. an object’s rotation) become broader with age, effectively widening the spectrum of stimuli that a single neuron responds to. Although research in humans has drawn on this finding as a potential mechanism for age-related dedifferentiation, it has not yet tested whether this process occurs for neural representations of continuous space. This presents a disconnect between the work on neural dedifferentiation in humans on the one hand, and animal work on its mechanisms on the other. The main goal of this dissertation was to address this disconnect and to further understand how aging shapes representations of continuous spaces. To achieve this, the three research articles that form the main body of this dissertation focus on the cognitive domains of spatial navigation and reinforcement learning. Article I analyzes functional magnetic resonance imaging (fMRI) data collected during virtual spatial navigation of older and younger adults and presents evidence that the phenomenon of age-related neural dedifferentiation in humans extends to representations of a continuous variable, namely walking direction. The results are based on a newly introduced analysis approach that allows the field to assess the similarity of neural responses towards stimuli stemming from the same continuous space. Article II combines a double-blind cross-over drug intervention with a design similar to article I and investigates the mechanistic role of the transmitter dopamine in age-related neural dedifferentiation. The study replicates the findings of article I and confirms the causal role of neuromodulation on the specificity of neural representations suggested by computational models. In particular, results show that the administration of L-DOPA, a dopamine precursor, enhances the specificity with which different walking directions are represented in the brain of younger and older adults. Finally, article III moves towards more abstract continuous space and uses a reinforcement learning paradigm to assess how a younger and older age group learn from surprising events. More specifically, it investigates if prediction errors, a continuous quantity reflecting the difference between an expected and obtained outcome of an action, are represented differently in learning and behavior of younger and older individuals. Behavioral results indicate that older adults showed heightened sensitivity to surprise compared to younger adults, overrepresenting the extreme end of the continuous space of prediction errors in their decisions. In summary, this thesis has made a number of contributions towards our understanding of how aging influences representations of continuous space. For one, it provides the first evidence of age-related neural dedifferentiation of a continuous variable in humans, based on a newly developed analysis approach. In doing so, it closes an important gap between related research in humans and non-human animals. It furthermore accounts for a key mechanism of dedifferentiation, confirming the causal influence of dopamine on the specificity of neural representations, as predicted by computational models. Finally, the thesis shows that diverging representations of continuous space in older adults also extend to the more abstract domain of outcome-based learning.Das menschliche Gehirn unterliegt im Laufe des Lebens bemerkenswerten Veränderungen, die sowohl strukturelle als auch funktionelle Eigenschaften betreffen. Eine funktionelle Veränderung, die insbesondere im Gehirn älteren Erwachsenen festgestellt wurde, ist das Phänomen der neuronalen Dedifferenzierung. Dies beschreibt einen Prozess, bei dem die nervlichen Reaktionen im Laufe des Alterns an Spezifität verlieren, so dass die neuronalen Repräsentationen z.B. verschiedener visueller Kategorien einander immer ähnlicher werden. Untersuchungen an Tieren haben gezeigt, dass die Reaktionsprofile neuronaler Populationen über einen kontinuierlichen Reizraum (z.B. die Drehung eines Objekts) mit zunehmendem Alter breiter werden, wodurch sich das Spektrum der Reize, auf die ein einzelnes Neuron reagiert, effektiv erweitert. Obwohl die Forschung am Menschen auf diesen Befund als einen der möglichen zugrundeliegenden Mechanismen hingewiesen hat, konnte eine altersbedingte Dedifferenzierung bisher nicht für neuronale Repräsentationen eines kontinuierlichen Raums nachgewiesen werden. Dies stellt eine Diskrepanz zwischen den Arbeiten zur neuronalen Dedifferenzierung beim Menschen einerseits und den Arbeiten zu den zugehörigen Mechanismen bei Tieren andererseits dar. Das Hauptziel dieser Dissertation war es, diese Diskrepanz zu beseitigen und besser zu verstehen, wie das Altern die Repräsentation von kontinuierlichen Räumen formt. Um dies zu erreichen, konzentrieren sich die drei Forschungsartikel, die den Hauptteil dieser Dissertation bilden, auf die kognitiven Bereiche der räumlichen Navigation und des Verstärkungslernens. In Artikel I analysiere ich Daten der funktionellen Magnetresonanztomographie (fMRI), die während der virtuellen räumlichen Navigation älterer und jüngerer Erwachsener erhoben wurden. Ich präsentiere Belege dafür, dass das Phänomen der altersbedingten neuronalen Dedifferenzierung beim Menschen auch Repräsentation einer kontinuierlichen Variable, nämlich der Laufrichtung, betrifft. Die Ergebnisse basieren auf einem neu eingeführten Analyseansatz, der es erlaubt, die Ähnlichkeit der neuronalen Reaktionen auf Reize zu bewerten, die aus dem- selben kontinuierlichen Raum stammen. Artikel II kombiniert eine doppelblinde Cross-over-Medikamentenintervention mit einem ähnlichen Design wie Artikel I und untersucht die mechanistische Rolle des Transmitters Dopamin bei altersbedingter neuronaler Dedifferenzierung. Die Studie repliziert die Ergebnisse von Artikel I und bestätigt die kausale Rolle der Neuromodulation auf die Spezifität der neuronalen Repräsentationen, wie sie von Computermodellen vorhergesagt wurde. Insbesondere zeigen die Ergebnisse, dass die Verabreichung von L-DOPA, einer Dopaminvorstufe, die Spezifität mit der verschiedene Laufrichtungen im Gehirn von jüngeren und älteren Erwachsenen repräsentiert werden erhöht. Artikel III schließlich befasst sich mit einem abstrakteren kontinuierlichen Raum und verwendet ein Paradigma des Verstärkungslernens, um zu untersuchen, wie sich jüngere und ältere Menschen beim Lernen von überraschenden Ereignissen unterscheiden. Genauer gesagt wird untersucht, ob Vorhersagefehler, eine kontinuierliche Größe, die die Differenz zwischen der erwarteten und der erhaltenen Belohnung einer Handlung widerspiegelt, im Lernen und Verhalten von jüngeren und älteren Personen unterschiedlichen Einfluss nehmen. Die Ergebnisse zeigen, dass ältere Erwachsene im Vergleich zu jüngeren Erwachsenen eine erhöhte Empfindlichkeit gegenüber überraschenden Belohnungen zeigen und, dass das extreme Ende des Kontinuums der Vorhersagefehler in ihren Entscheidungen größeren Einfluss nimmt. Zusammenfassend lässt sich sagen, dass diese Arbeit eine Reihe von Beiträgen zu unserem Verständnis darüber geleistet hat, wie das Altern die Repräsentationen des kontinuierlichen Raums beeinflusst. Zum einen liefert sie auf der Grundlage eines neu entwickelten Analyseansatzes den ersten Nachweis für altersbedingte neuronale Dedifferenzierung im Kontext einer kontinuierlichen Variable. Damit schließt sie eine wichtige Lücke zwischen verwandten Arbeiten in Menschen und nicht-menschlichen Tieren. Bezüglich der Mechanismen der neuronalen Dedifferenzierung bestätigt sie darüber hinaus den kausalen Einfluss von Dopamin auf die Spezifität neuronaler Repräsentationen, wie von Computermodellen vorhergesagt. Schließlich zeigt die Arbeit, dass divergierende Repräsentationen des kontinuierlichen Raums bei älteren Erwachsenen auch im abstrakteren Bereich des ergebnisbasierten Lernens präsent sind