Neuroscience seminars

Neural integrators are circuits that are able to code analog information such as spatial location or amplitude. Storing amplitude requires the network to have a large number of attractors. In classic models with recurrent excitation, such networks require very careful tuning to behave as integrators and are not robust to small mistuning of the recurrent weights. In this talk, I introduce a circuit with recurrent connectivity that is subjected to a slow subthreshold oscillation (such as the theta rhythm in the hippocampus). I show that such a network can robustly maintain many discrete attracting states. Furthermore, the firing rates of the neurons in these attracting states are much closer to those seen in recordings of animals. I show the mechanism for this can be explained by the instability regions of the Mathieu equation. I then extend the model in various ways and, for example, show that in a spatially distributed network, it is possible to code location and amplitude simultaneously. I show that the resulting mean field equations are equivalent to a certain discontinuous differential equation.

In this talk I will summarize some of our recent unpublished work on spectral coding in the larval zebrafish retina. Combining 2p imaging, hyperspectral stimulation, computational modeling and connectomics, we take a renewed look at the spectral tuning of cone photoreceptors in the live eye. We find that already cones optimally rotate natural colour space in a PCA-like fashion to disambiguate greyscale from "colour" information. We then follow this signal through the retinal layers and ultimately into the brain to explore the major spectral computations performed by the visual system at its consecutive stages. We find that by and large, zebrafish colour vision can be broken into three major spectral zones: long wavelength grey-scale-like vision, short-wavelength prey capture circuits, and spectrally diverse mid-wavelength circuits which possibly support the bulk of "true colour vision" in this tetrachromate vertebrate.

Se planteara un panorama historico asi como una descrpicion actual de la salud cerebral en Uruguay, se describiran las lineas de accion fundamentales desde el msp para la prevencion, tratamiento, rehabilitacion e investigacion de lops problemas neurologicos en Uruguay

To organize various experiences in a coherent mental representation, we need to properly estimate the duration and temporal order of different events. Yet, our perception of time is noisy and vulnerable to various illusions. Studying these illusions can elucidate the mechanism by which the brain perceives time. In this talk, I will review a few studies on how the brain perceives duration of events and the temporal order between self-generated motion and sensory feedback. Combined with computational models at different levels, these experiments illustrated that the brain incorporates the prior knowledge of the statistical distribution of the duration of stimuli and the decay of memory when estimating duration of an individual event, and adjusts its perception of temporal order to changes in the statistics of the environment.

Computational and cognitive neuroscience techniques have made great strides towards describing the neural computations underlying perceptual inference and decision-making under uncertainty. These tools tell us how and why perceptual illusions occur, which brain areas may represent noisy information in a probabilistic manner, and so on. However, an understanding of the subjective, qualitative aspects of perception remains elusive: qualia, or the personal, intrinsic properties of phenomenal awareness, have remained out of reach of these computational analytic insights. Here, I propose that metacognitive computations, and the subjective feelings that go along with them, give us a solid starting point for understanding subjective experience in general. Specifically, perceptual metacognition possesses ontological and practical properties that provide a powerful and unique opportunity for studying the studying the neural and computational correlates of subjective experience using established tools of computational and cognitive neuroscience. By capitalizing on decades of developments in formal computational model comparisons as applied to the specific properties of perceptual metacognition, we are now in a privileged position to reveal new and exciting insights about how the brain constructs our subjective conscious experiences.

The Manookin lab is investigating the structure and function of neural circuits within the retina and developing techniques for treating blindness. Many blinding diseases, such as retinitis pigmentosa, cause death of the rods and cones, but spare other cell types within the retina. Thus, many techniques for restoring visual function following blindness are based on the premise that other cells within the retina remain viable and capable of performing their various roles in visual processing. There are more than 80 different neuronal types in the human retina and these form the components of the specialized circuits that transform the signals from photoreceptors into a neural code responsible for our perception of color, form, and motion, and thus visual experience. The Manookin laboratory is investigating the function and connectivity of neural circuits in the retina using a variety of techniques including electrophysiology, calcium imaging, and electron microscopy. This knowledge is being used to develop more effective techniques for restoring visual function following blindness.

In a cross wind, the direction a fly moves through the air may differ from its heading direction, the direction defined by its body axis. I will present a model based on experimental results that reveals how a heading direction “compass” signal is combined with optic flow to compute and represent the direction that a fly is traveling. This provides a general framework for understand how flies perform vector computations.

Genetic targeting of neuronal cells with activity reporters (calcium or voltage indicators) has initiated the paradigmatic transition whereby photons have replaced electrons for reading large-scale brain activities at cellular resolution. This has alleviated the limitations of single cell or extracellular electrophysiological probing, which only give access to the activity of at best a few neurons simultaneously and to population activity of unresolved cellular origin, respectively. In parallel, optogenetics has demonstrated that targeting neuronal cells with photosensitive microbial opsins, enables the transduction of photons into electrical currents of opposite polarities thus writing, through activation or inhibition, neuronal signals in a non-invasive way. These progresses have in turn stimulated the development of sophisticated optical methods to increase spatial and temporal resolution, light penetration depth and imaging volume. Today, nonlinear microscopy, combined with spatio-temporal wave front shaping, endoscopic probes engineering or multi scan heads design, enable in vivo in depth, simultaneous recording of thousands of cells in mm 3 volumes at single-spike precision and single-cell resolution. Joint progress in opsin engineering, wave front shaping and laser development have provided the methodology, that we named circuits optogenetics, to control single or multiple target activity independently in space and time with single- neuron and single-spike precision, at large depths. Here, we will review the most significant breakthroughs of the past years, which enable reading and writing neuronal activity at the relevant spatiotemporal scale for brain circuits manipulation, with particular emphasis on the most recent advances in circuit optogenetics.

Interoception, the sense of internal bodily signals, is essential for physiological homeostasis, cognition, and emotions. Human neuroimaging studies suggest insular cortex plays a central role in interoception, yet the cellular and circuit mechanisms of its involvement remain unclear. We developed a microprism-based cellular imaging approach to monitor insular cortex activity in behaving mice across different physiological need states. We combine this imaging approach with manipulations of peripheral physiology, circuit-mapping, cell type-specific and circuit-specific manipulation approaches to investigate the underlying circuit mechanisms. I will present our recent data investigating insular cortex activity during two physiological need states – hunger and thirst. These wereinduced naturally by caloric/fluid deficiency, or artificially by activation of specific hypothalamic “hunger neurons” and “thirst neurons”. We found that insular cortex ongoing activity faithfully represents current physiological state, independently of behavior or arousal levels. In contrast, transient responses to learned food- or water-predicting cues reflect a population-level “simulation” of future predicted satiety. Together with additional circuit-mapping and manipulation experiments, our findings suggest that insular cortex integrates visceral-sensory inputs regarding current physiological state with hypothalamus-gated amygdala inputs signaling availability of food/water. This way, insular cortex computes a prediction of future physiological state that can be used to guide behavioral choice.

This presentation will include a brief resume of research in older populations led from Cambridge that have informed current clinical understanding and policy regarding services and prevention for and of dementia. These population studies have more recently been ‘re-purposed’ with enthusiasm from participants into a trial platform, and this also has enabled ongoing follow-up by telephone during the COVID pandemic. Although there are no formal outputs from these latter developments general impressions will be shared.

After an injury in the adult mammalian central nervous system, lesioned axons fail to regenerate. This failure to regenerate contrasts with the remarkable potential of axons to grow during embryonic development and after an injury in the peripheral nervous system. Peripheral sensory neurons with cell soma in dorsal root ganglia (DRG) switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Decades of research have focused on the signaling pathways elicited by injury in sensory neurons and in Schwann cells that insulate axons as central mechanisms regulating nerve repair. However, neuronal microenvironment is far more complex and is composed of multiple cell types including endothelial, immune and glial cells. Whether the microenvironment surrounding neuronal soma contribute to the poor regenerative outcomes following central injuries remains largely unexplored. To answer this question, we performed a single cell transcriptional profiling of the DRG neuronal microenvironment response to peripheral and central injuries. In dissecting the roles of the microenvironment contribution, we have focused on a poorly studied population of Satellite Glial Cells (SGC) surrounding the neuronal cell soma. This study has uncovered a previously unknown role for SGC in nerve regeneration and defined SGC as transcriptionally distinct from Schwann cells while sharing similarities with astrocytes. Upon a peripheral injury, SGC contribute to axon regeneration via Fatty acid synthase (Fasn)-PPARα signaling pathway. Through repurposing fenofibrate, an FDA- approved PPARα agonist used for dyslipidemia treatment, we were able to rescue the impaired regeneration in mice lacking Fasn in SGC. Our analysis reveals that in response to central injuries, SGC do not activate the PPAR signaling pathway. However, induction of this pathway with fenofibrate treatment, rescued axon regeneration following an injury to the central nerves. Collectively, our results uncovered a previously unappreciated role of the neuronal microenvironment differential response in central and peripheral injuries.

Corticospinal neurons (CSN) are the cortical projection neurons that innervate the spinal cord and some brainstem targets with segmental precision to control voluntary movement of specific functional motor groups, limb sections, or individual digits, yet molecular regulation over CSN segmental target specificity is essentially unknown. CSN subpopulations exhibit striking axon targeting specificity from development into maturity: Evolutionarily newer rostrolateral CSN exclusively innervate bulbar-cervical targets (CSNBC-lat), while evolutionarily older caudomedial CSN (CSNmed) are more heterogeneous, with distinct subpopulations extending axons to either bulbar-cervical or thoraco-lumbar segments. The cervical cord, with its evolutionarily enhanced precision of forelimb movement, is innervated by multiple CSN subpopulations, suggesting inter-neuronal interactions in establishing corticospinal connectivity. I identify that Lumican, previously unrecognized in axon development, controls the specificity of cervical spinal cord innervation by CSN. Remarkably, Lumican, an extracellular matrix protein expressed by CSNBC-lat, non-cell-autonomously suppresses axon collateralization in the cervical cord by CSNmed. Intersectional viral labeling and mouse genetics further identify that Lumican controls axon collateralization by multiple subpopulations in caudomedial sensorimotor cortex. These results identify inter-axonal molecular crosstalk between CSN subpopulations as a novel mechanism controlling corticospinal connectivity and competitive specificity. Further, this mechanism has potential implications for evolutionary diversification of corticospinal circuitry with finer scale precision. "" Complementing this work, to comprehensively elucidate related axon projection mechanisms functioning at tips of growing CSN axons in vivo, I am currently applying experimental and analytic approaches recently developed in my postdoc lab (Poulopoulos*, Murphy*, Nature, 2019) to quantitatively and subcellularly “map” RNA and protein molecular machinery of subtype-specific growth cones, in parallel to their parent somata, isolated directly in vivo from developing subcerebral projection neurons (SCPN; the broader cortical output neuron population targeting both brainstem and spinal cord; includes CSN). I am investigating both normal development and GC-soma dysregulation with mutation of central CSN-SCPN transcriptional regulator Ctip2/Bcl11b.

We will start our talk with a short video of our research, illustrating methods (some old and new) and findings that have provided our current understanding of how visual capabilities develop in infancy and early childhood. However, our research poses some outstanding questions. We will briefly discuss three issues, which are linked by a common focus on the development of visual attentional processing: (1) How do recurrent cortical loops contribute to development? Cortical selectivity (e.g., to orientation, motion, and binocular disparity) develops in the early months of life. However, these systems are not purely feedforward but depend on parallel pathways, with recurrent feedback loops playing a critical role. The development of diverse networks, particularly for motion processing, may explain changes in dynamic responses and resolve developmental data obtained with different methodologies. One possible role for these loops is in top-down attentional control of visual processing. (2) Why do hyperopic infants become strabismic (cross-eyes)? Binocular interaction is a particularly sensitive area of development. Standard clinical accounts suppose that long-sighted (hyperopic) refractive errors require accommodative effort, putting stress on the accommodation-convergence link that leads to its breakdown and strabismus. Our large-scale population screening studies of 9-month infants question this: hyperopic infants are at higher risk of strabismus and impaired vision (amblyopia and impaired attention) but these hyperopic infants often under- rather than over-accommodate. This poor accommodation may reflect poor early attention processing, possibly a ‘soft sign’ of subtle cerebral dysfunction. (3) What do many neurodevelopmental disorders have in common? Despite similar cognitive demands, global motion perception is much more impaired than global static form across diverse neurodevelopmental disorders including Down and Williams Syndromes, Fragile-X, Autism, children with premature birth and infants with perinatal brain injury. These deficits in motion processing are associated with deficits in other dorsal stream functions such as visuo-motor co-ordination and attentional control, a cluster we have called ‘dorsal stream vulnerability’. However, our neuroimaging measures related to motion coherence in typically developing children suggest that the critical areas for individual differences in global motion sensitivity are not early motion-processing areas such as V5/MT, but downstream parietal and frontal areas for decision processes on motion signals. Although these brain networks may also underlie attentional and visuo-motor deficits , we still do not know when and how these deficits differ across different disorders and between individual children. Answering these questions provide necessary steps, not only increasing our scientific understanding of human visual brain development, but also in designing appropriate interventions to help each child achieve their full potential.

We are interested in understanding how microbes impact the behavior of host animals. Animal nervous systems likely evolved in environments richly surrounded by microbes, yet the impact of bacteria on nervous system function has been relatively under-studied. A challenge has been to identify systems in which both host and microbe are amenable to genetic manipulation, and which enable high-throughput behavioral screening in response to defined and naturalistic conditions. To accomplish these goals, we use an animal host — the roundworm C. elegans, which feeds on bacteria — in combination with its natural gut microbiome to identify inter-organismal signals driving host-microbe interactions and decision-making. C. elegans has some of the most extensive molecular, neurobiological and genetic tools of any multicellular eukaryote, and, coupled with the ease of gnotobiotic culture in these worms, represents a highly attractive system in which to study microbial influence on host behavior. Using this system, we discovered that commensal bacterial metabolites directly modulate nervous system function of their host. Beneficial gut microbes of the genus Providencia produce the neuromodulator tyramine in the C. elegans intestine. Using a combination of behavioral analysis, neurogenetics, metabolomics and bacterial genetics we established that bacterially produced tyramine is converted to octopamine in C. elegans, which acts directly in sensory neurons to reduce odor aversion and increase sensory preference for Providencia. We think that this type of sensory modulation may increase association of C. elegans with these microbes, increasing availability of this nutrient-rich food source for the worm and its progeny, while facilitating dispersal of the bacteria.