Several postdoctoral positions are available in the Complex Networks and Brain Dynamics group (COBRA) at the Institute of Computer Science, Prague (Czech Republic). These positions are part of a larger, interdisciplinary consortium project that has recently been awarded (OPJAK BRADY). The project topics include: Topic 1: Detailed biophysical modelling of neurotransmitter action (supervised by Pavel Sanda). Topic 2: Computationally efficient mean-field models of cortical microcircuits (supervised by Helmut Schmidt). Topic 3: Whole-brain dynamics with applications particularly to schizophrenia and Parkinson's disease (supervised by Gustavo Deco). Topic 4: Data-driven model inversion and personalized parameter identification (supervised by Nikola Jajcay). Topic 5: Modelling interventions into arousal dynamics (supervised by Jaroslav Hlinka). Other related topics may be considered based on their fit to the overall project.

Nervous system function relies on the polarized architecture of neurons, established by directional transport of pre- and postsynaptic cargoes. While delivery of postsynaptic components depends on the secretory pathway, the identity of the membrane compartment(s) that supply presynaptic active zone (AZ) and synaptic vesicle (SV) proteins is largely unknown. I will discuss our recent advances in our understanding of how key components of the presynaptic machinery for neurotransmitter release are transported and assembled focussing on our studies in genome-engineered human induced pluripotent stem cell-derived neurons. Specifically, I will focus on the composition and cell biological identity of the axonal transport vesicles that shuttle key components of neurotransmission to nascent synapses and on machinery for axonal transport and its control by signaling lipids. Our studies identify a crucial mechanism mediating the delivery of SV and active zone proteins to developing synapses and reveal connections to neurological disorders. In the second part of my talk, I will discuss how exocytosis and endocytosis are coupled to maintain presynaptic membrane homeostasis. I will present unpublished data regarding the role of membrane tension in the coupling of exocytosis and endocytosis at synapses. We have identified an endocytic BAR domain protein that is capable of sensing alterations in membrane tension caused by the exocytotic fusion of SVs to initiate compensatory endocytosis to restore plasma membrane area. Interference with this mechanism results in defects in the coupling of presynaptic exocytosis and SV recycling at human synapses.

Astrocytes release glutamate by regulated exocytosis in health and disease Vladimir Parpura, International Translational Neuroscience Research Institute, Zhejiang Chinese Medical University, Hangzhou, P.R. China Parpura will present you with the evidence that astrocytes, a subtype of glial cells in the brain, can exocytotically release the neurotransmitter glutamate and how this release is regulated. Spatiotemporal characteristic of vesicular fusion that underlie glutamate release in astrocytes will be discussed. He will also present data on a translational project in which this release pathway can be targeted for the treatment of glioblastoma, the deadliest brain cancer.

In most brains across the animal kingdom, brain dynamics can enter pathological states that are recognisable as epileptic seizures. Yet usually, brain operate within certain constraints given through neuronal function and synaptic coupling, that will prevent epileptic seizure dynamics from emerging. In this talk, I will bring together different approaches to identifying how networks in the broadest sense shape brain dynamics. Using illustrative examples from intracranial EEG recordings, disorders characterised by molecular disruption of a single neurotransmitter receptor type, to single-cell recordings of whole-brain activity in the larval zebrafish, I will address three key questions - (1) how does the regionally specific composition of synaptic receptors shape ongoing physiological brain activity; (2) how can disruption of this regionally specific balance result in abnormal brain dynamics; and (3) which cellular patterns underly the transition into an epileptic seizure.

Focal neocortical epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood, but is likely to relate to the intermittent collapse of feed-forward GABAergic inhibition. Inhibition could fail through multiple mechanisms, including (i) an attenuation or even reversal of the driving force for chloride in postsynaptic neurons because of intense activation of GABAA receptors, (ii) an elevation of potassium secondary to chloride influx leading to depolarization of neurons, or (iii) insufficient GABA release from interneurons. I shall describe the results of experiments using fluorescence imaging of calcium, glutamate or GABA in awake rodent models of neocortical epileptiform activity. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagatedcentrifugally. GABA transients lasted longer than glutamate transients and were maximal ~1.5 mm from the focus. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing runaway recruitment of excitatory neurons as a fundamental mechanism underlying the escape of seizures from local inhibitory restraint.

Within the vertebrate neocortex and other telencephalic structures, molecularly-defined neurons tend to segregate at first order into GABAergic types and glutamatergic types. Two fundamental questions arise: (1) do non-telencephalic neurons similarly segregate by neurotransmitter status, and (2) do GABAergic (or glutamatergic) types sampled in different structures share many molecular features in common, beyond the few genes directly responsible for neurotransmitter synthesis and release? To address these questions, we used single-nucleus RNA sequencing, analyzing over 2.4 million brain cells sampled from 16 locations in a primate (the common marmoset). Unexpectedly, we find the answer to both is “no”. I will discuss implications for generalizing associations between neurotransmitter utilization and other phenotypes, and share ongoing efforts to map the biodistributions of cell types in the primate brain.

Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs directly synapse onto neurons and the subsequent tumor cell depolarization, mediated by calcium-permeable AMPA channels, promotes their proliferation. The regulatory mechanisms governing these postsynaptic connections are unknown. Here, we investigated the role of BDNF-TrkB signaling in modulating the plasticity of the malignant synapse. BDNF ligand activation of its canonical receptor, TrkB (which is encoded for by the gene NTRK2), has been shown to be one important modulator of synaptic regulation in the normal setting. Electrophysiological recordings of glioma cell membrane properties, in response to acute neurotransmitter stimulation, demonstrate in an inward current resembling AMPA receptor (AMPAR) mediated excitatory neurotransmission. Extracellular BDNF increases the amplitude of this glutamate-induced tumor cell depolarization and this effect is abrogated in NTRK2 knockout glioma cells. Upon examining tumor cell excitability using in situ calcium imaging, we found that BDNF increases the intensity of glutamate-evoked calcium transients in GCaMP6s expressing glioma cells. Western blot analysis indicates the tumors AMPAR properties are altered downstream of BDNF induced TrkB activation in glioma. Cell membrane protein capture (via biotinylation) and live imaging of pH sensitive GFP-tagged AMPAR subunits demonstrate an increase of calcium permeable channels at the tumors postsynaptic membrane in response to BDNF. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis as measured by high-resolution confocal and electron microscopy in culture and tumor xenografts. Our analysis of published pHGG transcriptomic datasets, together with brain slice conditioned medium experiments in culture, indicates the tumor microenvironment as the chief source of BDNF ligand. Disruption of the BDNF-TrkB pathway in patient-derived orthotopic glioma xenograft models, both genetically and pharmacologically, results in an increased overall survival and reduced tumor proliferation rate. These findings suggest that gliomas leverage normal mechanisms of plasticity to modulate the excitatory channels involved in synaptic neurotransmission and they reveal the potential to target the regulatory components of glioma circuit dynamics as a therapeutic strategy for these lethal cancers.

Synaptic transmission provides the basis for neuronal communication. When an action-potential propagates through the axonal arbour, it activates voltage-gated Ca2+ channels located in the vicinity of release-ready synaptic vesicles docked at the presynaptic active zone. Ca2+ ions enter the presynaptic terminal and activate the vesicular Ca2+ sensor, thereby triggering neurotransmitter release. This whole process occurs on a timescale of a few milliseconds. In addition to fast, synchronous release, which keeps pace with action potentials, many synapses also exhibit delayed asynchronous release that persists for tens to hundreds of milliseconds. In this talk I will demonstrate how experimentally constrained computational modelling of underlying biological processes can complement laboratory studies (using electrophysiology and imaging techniques) and provide insights into the mechanisms of synaptic transmission.

MicroRNAs are small noncoding RNAs that provide a critical layer of gene expression control. Individual microRNAs variably exert effects across networks of genes via sequence-specific binding to mRNAs, fine-tuning protein levels. This helps coordinate the timing and specification of cell fate transitions during brain development and maintains neural circuit function and plasticity by activity-dependent (re)shaping of synapses and the levels of neurotransmitter components. MicroRNA levels have been found to be altered in tissue from the epileptogenic zone resected from adults with drug-resistant focal epilepsy and this has driven efforts to explore their therapeutic potential, in particular using antisense oligonucleotide (ASOs) inhibitors termed antimirs. Here, we review the molecular mechanisms by which microRNAs control brain excitability and the latest progress towards a microRNA-based treatment for temporal lobe epilepsy. We also look at whether microRNA-based approaches could be used to treat genetic epilepsies, correcting individual genes or dysregulated pathways. Finally, we look at how cells have evolved to maximise the efficiency of the microRNA system via RNA editing, where single base changes is capable of altering the repertoire of genes under the control of a single microRNA. The findings improve our understanding of the molecular landscape of the epileptic brain and may lead to new therapies.

Dr. Looger will present updates on a variety of molecular tools for studying & manipulating neural circuits & other preparations. Topics include genetically encoded calcium indicators (including the new ultra-fast jGCaMP8 variants), neurotransmitter sensors (improved versions for following glutamate, GABA, acetylcholine, serotonin), optogenetic effectors including the new “enhanced Magnets” dimerizers, AAV serotypes for retrograde labeling & altered tropism, probes for correlative light-electron microscopy, chemical gene switches, etc. He will make all his slides freely available - so don’t worry about hurriedly taking notes; instead focus on questions and ideas for collaboration. Please bring your suggestions for molecular tools that would be transformative for the field.

Neurons in the suprachiasmatic nucleus (SCN, the brain’s master circadian clock) display a 24 hour cycle in the their rate of action potential discharge whereby firing rates are high during the light phase and lower during the dark phase. Although it is generally agreed that this cycle of activity is a key mediator of the clock’s neural and humoral output, surprisingly little is known about how changes in clock electrical activity can mediate scheduled physiological changes at different times of day. Using opto- and chemogenetic approaches in mice we have shown that the onset of electrical activity in vasopressin releasing SCN neurons near Zeitgeber time 22 (ZT22) activates glutamatergic thirst-promoting neurons in the OVLT (organum vasculosum lamina terminalis) to promote water intake prior to sleep. This effect is mediated by activity-dependent release of vasopressin from the axon terminals of SCN neurons which acts as a neurotransmitter on OVLT neurons. More recently we found that the clock receives excitatory input from a different subset of sodium sensing neurons in the OVLT. Activation of these neurons by a systemic salt load delivered at ZT19 stimulated the electrical activity of SCN neurons which are normally silent at this time. Remarkably, this effect induced an acute reduction in non-shivering thermogenesis and body temperature, which is an adaptive response to the salt load. These findings provide information regarding the mechanisms by which the SCN promotes scheduled physiological rhythms and indicates that the clock’s output circuitry can also be recruited to mediate an unscheduled homeostatic response.

Accurate and synchronous neurotransmitter release is essential for brain communication and occurs when neurotransmitter-containing synaptic vesicles (SVs) fuse to release their content in response to neuronal activity. Neurotransmission is sustained by the process of SV recycling, which generates SVs locally at the presynapse. Until relatively recently it was believed that most mutations in genes that were essential for SV recycling would be incompatible with life, due to this fundamental role. However, this is not the case, with mutations in essential genes for SV fusion, retrieval and recycling identified in individuals with epilepsy. This seminar will cover our laboratory’s progress in determining how genetic mutations in people with epilepsy translate into presynaptic dysfunction and ultimately into seizure activity. The principal focus of these studies will be in vitro investigations of, 1) the biological role of these gene products and 2) how their dysfunction impacts SV recycling, using live fluorescence imaging of genetically-encoded reporters. The gene products to be discussed in more detail will be the SV protein SV2A, the protein kinase CDKL5 and the translation repressor FMRP.

The CNS is responsive to an ever-changing environment. Until recently, studies of neural plasticity focused almost exclusively on functional and structural changes of neuronal synapses. In recent years, myelin plasticity has emerged as a potential modulator of neural networks. Myelination of previously unmyelinated axons, and changes in the structure on already-myelinated axons, can have large effects on network function. The heterogeneity of the extent of how axons in the CNS are myelinated offers diverse scope for dynamic myelin changes to fine-tune neural circuits. The traditionally held view of myelin as a passive insulator of axons is now changing to one of lifelong changes in myelin, modulated by neuronal activity and experience. Myelin, produced by oligodendrocytes (OLs), is essential for normal brain function, as it provides fast signal transmission, promotes synchronization of neuronal signals and helps to maintain neuronal function. OLs differentiate from oligodendrocyte precursor cells (OPCs), which are distributed throughout the adult brain, and myelination continues into late adulthood. OPCs can sense neuronal activity as they receive synaptic inputs from neurons and express voltage-gated ion channels and neurotransmitter receptors, and differentiate into myelinating OLs in response to changes in neuronal activity. This lecture will explore to what extent myelin plasticity occurs in adult animals, whether myelin changes occur in non-motor learning tasks, especially in learning and memory, and questions whether myelin plasticity and myelin regeneration are two sides of the same coin.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1% of over 65's; there is currently no effective treatment. Dopaminergic neuronal loss is hallmark in PD and yet despite decades of intensive research there is still no known therapeutic which will completely halt the disorder. As a result, identification of interventive therapies to reverse or prevent PD are essential. Using genetically faithful models (induced pluripotent stem cells and knock-in mice) of familial late onset PD (LRRK2 G2019S and GBA N370S) we have contributed to the literature that neuronal dysfunction precedes degeneration. Specifically, using whole cell patch clamp electrophysiology, biochemical, behavioural and molecular biological techniques, we have begun to investigate the fundamental processes that make neurons specialised i.e., synaptic function and neurotransmission. We illustrate those alterations to spontaneous neurotransmitter release, neuronal firing, and short-term plasticity as well as Ca2+ and energy dyshomeostasis, are some of the earliest observable pathological dysfunctions and are likely precursors to late-stage degeneration. These pathologies represent targets which can be manipulated to address causation, rather than the symptoms of the PD, and represent a marker that, if measurable in patients, could form the basis of early PD detection and intervention.

CA3-CA1 synapses in the hippocampus are the initial locus of episodic memory. The action of acetylcholine alters cellular excitability, modifies neuronal networks, and triggers secondary signaling that directly affects long-term plasticity (LTP) (the cellular underpinning of memory). It is therefore considered a critical regulator of learning and memory in the brain. Its action via M4 metabotropic receptors in the presynaptic terminal of the CA3 neurons and M1 metabotropic receptors in the postsynaptic spines of CA1 neurons produce rich dynamics across multiple timescales. We developed a model to describe the activation of postsynaptic M1 receptors that leads to IP3 production from membrane PIP2 molecules. The binding of IP3 to IP3 receptors in the endoplasmic reticulum (ER) ultimately causes calcium release. This calcium release from the ER activates potassium channels like the calcium-activated SK channels and alters different aspects of synaptic signaling. In an independent signaling cascade, M1 receptors also directly suppress SK channels and the voltage-activated KCNQ2/3 channels, enhancing post-synaptic excitability. In the CA3 presynaptic terminal, we model the reduction of the voltage sensitivity of voltage-gated calcium channels (VGCCs) and the resulting suppression of neurotransmitter release by the action of the M4 receptors. Our results show that the reduced initial release probability because of acetylcholine alters short-term plasticity (STP) dynamics. We characterize the dichotomy of suppressing neurotransmitter release from CA3 neurons and the enhanced excitability of the postsynaptic CA1 spine. Mechanisms underlying STP operate over a few seconds, while those responsible for LTP last for hours, and both forms of plasticity have been linked with very distinct functions in the brain. We show that the concurrent suppression of neurotransmitter release and increased sensitivity conserves neurotransmitter vesicles and enhances the reliability in plasticity. Our work establishes a relationship between STP and LTP coordinated by neuromodulation with acetylcholine.

In this presentation, we will discuss the cellular and molecular properties of the retrotrapezoid nucleus (RTN), an integrative and interoceptive control node for the respiratory motor system. We will present the molecular profiling that has allowed definitive identification of a cluster of tonically active neurons that provide a requisite drive to the respiratory central pattern generator (CPG) and other pre-motor neurons. We will discuss the ionic basis for steady pacemaker-like firing, including by a large subthreshold oscillation; and for neuromodulatory influences on RTN activity, including by arousal state-dependent neurotransmitters and CO2/H+. The CO2/H+-dependent modulation of RTN excitability represents the sensory component of a homeostatic system by which the brain regulates breathing to maintain blood gases and tissue pH; it relies on two intrinsic molecular proton detectors, both a proton-activated G protein-coupled receptor (GPR4) and a proton-inhibited background K+ channel (TASK-2). We will also discuss downstream neurotransmitter signaling to the respiratory CPG, focusing especially on a newly-identified peptidergic modulation of the preBötzinger complex that becomes activated following birth and the initiation of air breathing. Finally, we will suggest how the cellular and molecular properties of RTN neurons identified in rodent models may contribute to understanding human respiratory disorders, such as congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS).

My research uses a range of methods to better understand how the brain’s natural chemicals control complex behaviours, thoughts and perceptions. I also have a particular fascination about the factors that determine the contents of an individual’s conscious experience. In this talk I will present work that sits at the intersection of these two research areas looking at the role of different neurotransmitter systems in driving changes in conscious state. Specifically, I will discuss a series of studies using ambiguous stimuli to explore the neuropharmacological processes that underly alternations in perceptual awareness. By comparing different methods and neurotransmitter systems including: serotonin (psychedelics), noradrenaline (pupillometry) and Glutamate/GABA (Magnetic Resonance Spectroscopy MRS) we can start to tease apart the distinct role that different neurotransmitter systems play in coordinating conscious experience across time.

Developmental and epileptic encephalopathies (DEEs) are a broad spectrum of genetic epilepsies associated with impaired neurological development as a direct consequence of a genetic mutation, in addition to the effect of the frequent epileptic activity on brain. Compelling genetic studies indicate that heterozygous de novo mutations represent the most common underlying genetic mechanism, in accordance with the sporadic presentation of DEE. De novo mutations may exert a loss-of-function (LOF) on the protein by decrementing expression level and/or activity, leading to functional haploinsufficiency. These diseases share several features: severe and frequent refractory seizures, diffusely abnormal background activity on EEG, intellectual disability often profound, and severe consequences on global development. One of major causes of early onset DEE are de novo heterozygous mutations in syntaxin-binding-protein-1 gene STXBP1, which encodes a membrane trafficking protein playing critical role in vesicular docking and fusion. LOF STXBP1 mutations lead to a failure of neurotransmitter secretion from synaptic vesicles. Core clinical features of STXBP1 encephalopathy include early-onset epilepsy with hypsarrhythmic EEG, or burst-suppression pattern, or multifocal epileptiform activity. Seizures are often resistant to standard treatments and patients typically show intellectual disability, mostly severe to profound. Additional neurologic features may include autistic traits, movement disorders (dyskinesia, dystonia, tremor), axial hypotonia, and ataxia, indicating a broader neurologic impairment. Patients with severe neuro-cognitive features but without epilepsy have been reported. Recently, a new class of natural and synthetic non-coding RNAs have been identified, enabling upregulation of protein translation in a gene-specific way (SINEUPs), without any increase in mRNA of the target gene. SINEUPs are translational activators composed by a Binding Domain (BD) that overlaps, in antisense orientation, to the sense protein-coding mRNA, and determines target selection; and an Effector Domain (ED), that is essential for protein synthesis up regulation. SINEUPs have been shown to restore the physiological expression of a protein in case of haploinsufficiency, without driving excessive overexpression out of the physiological range. This technology brings many advantages, as it mainly acts on endogenous target mRNAs produced in situ by the wild-type allele; this action is limited to mRNA under physiological regulation, therefore no off-site effects can be expected in cells and tissues that do not express the target transcript; by acting only on a posttranscriptional level, SINEUPs do not trigger hereditable genome editing. After bioinformatic analysis of the promoter region of interest, we designed SINEUPs with 3 different BD for STXBP1. Human neurons from iPSCs were treated and STXBP1 levels showed a 1.5-fold increase compared to the Negative control. RNA levels of STXBP1 after the administration of SINEUPs remained stable as expected. These preliminary results proved the SINEUPs potential to specifically increase the protein levels without impacting on the genome. This is an extremely flexible approach to target many developmental and epileptic encephalopathies caused by haploinsufficiency, and therefore to address these diseases in a more tailored and radical way.

The development and maintenance of many tissues are fueled by stem cells. Many studies have addressed how intrinsic factors and local signals from neighboring niche cells maintain stem cell identity and proliferative potential. In contrast, it is poorly understood how stem cell activity is controlled by systemic, tissue-extrinsic signals in response to environmental cues and changes in physiological status. Our laboratory has been focusing on female germline stem cells (fGSCs) in the fruit fly Drosophila melanogaster as a model system and studying neuroendocrine control of fGSC increase. The increase of fGSCs is induced by mating stimuli. We have previously reported that mating-induced fGSC increase is regulated by the ovarian steroid hormone and the enteroendocrine peptide hormone [Ameku & Niwa, PLOS Genetics 2016; Ameku et al. PLOS Biology 2018]. In this presentation, we report our recent finding showing a neuronal mechanism of mating-induced fGSC increase. We first found that the ovarian somatic cell-specific RNAi for Oamb, a G protein-coupled receptor for the neurotransmitter octopamine, failed to induce fGSC proliferation after mating. Both ex vivo and in vivo experiments revealed that octopamine and Oamb positively regulated mating-induced fGSC increase via intracellular Ca 2+ signaling. We also found that a small subset of octopaminergic neurons directly projected to the ovary, and neuronal activity of these neurons was required for mating-induced fGSC increase. This study provides a mechanism describing how the neuronal system controls stem cell behavior through stem cell niche signaling [Yoshinari et al. eLife 2020]. Here I will also present our recent data showing how the neuroendocrine system couples fGSC behavior to multiple environmental cues, such as mating and nutrition.

Neurons in the primary visual cortex (V1) encode the orientation and contrast of visual stimuli through changes in firing rate (Hubel and Wiesel, 1962). Their activity typically peaks at a preferred orientation and decays to zero at the orientations that are orthogonal to the preferred. This activity pattern is re-scaled by contrast but its shape is preserved, a phenomenon known as contrast invariance. Contrast-invariant selectivity is also observed at the population level in V1 (Carandini and Sengpiel, 2004). The mechanisms supporting the emergence of contrast-invariance at the population level remain unclear. How does the activity of different neurons with diverse orientation selectivity and non-linear contrast sensitivity combine to give rise to contrast-invariant population selectivity? Theoretical studies have shown that in the balance limit, the properties of single-neurons do not determine the population activity (van Vreeswijk and Sompolinsky, 1996). Instead, the synaptic dynamics (Mongillo et al., 2012) as well as the intracortical connectivity (Rosenbaum and Doiron, 2014) shape the population activity in balanced networks. We report that short-term plasticity can change the synaptic strength between neurons as a function of the presynaptic activity, which in turns modifies the population response to a stimulus. Thus, the same circuit can process a stimulus in different ways –linearly, sublinearly, supralinearly – depending on the properties of the synapses. We found that balanced networks with excitatory to excitatory short-term synaptic plasticity cannot be contrast-invariant. Instead, short-term plasticity modifies the network selectivity such that the tuning curves are narrower (broader) for increasing contrast if synapses are facilitating (depressing). Based on these results, we wondered whether balanced networks with plastic synapses (other than short-term) can support the emergence of contrast-invariant selectivity. Mathematically, we found that the only synaptic transformation that supports perfect contrast invariance in balanced networks is a power-law release of neurotransmitter as a function of the presynaptic firing rate (in the excitatory to excitatory and in the excitatory to inhibitory neurons). We validate this finding using spiking network simulations, where we report contrast-invariant tuning curves when synapses release the neurotransmitter following a power- law function of the presynaptic firing rate. In summary, we show that synaptic plasticity controls the type of non-linear network response to stimulus contrast and that it can be a potential mechanism mediating the emergence of contrast invariance in balanced networks with orientation-dependent connectivity. Our results therefore connect the physiology of individual synapses to the network level and may help understand the establishment of contrast-invariant selectivity.

The neurotransmitter dopamine is essential for normal reward learning and motivational arousal processes. Indeed these core functions are implicated in the major neurological and psychiatric dopamine disorders such as schizophrenia, substance abuse disorders/addiction and Parkinson's disease. Over the years, we have made significant strides in understanding the dopamine system across multiple levels of description, and I will focus on our recent advances in the computational description, and brain circuit mechanisms that facilitate the dual role of dopamine in learning and performance. I will specifically describe our recent work with imaging the activity of dopamine axons and measurements of dopamine release in mice performing various behavioural tasks. We discovered wave-like spatiotemporal activity of dopamine in the striatal region, and I will argue that this pattern of activation supports a critical computational operation; spatiotemporal credit assignment to regional striatal subexperts. Our findings provide a mechanistic description for vectorizing reward prediction error signals relayed by dopamine.

How does the presence or absence of food shape and prioritize behavioral decisions? When is food more than just food? As in other animals, prolonged food deprivation dramatically alters sensory behaviors in C. elegans. For instance, it has been known since the mid-1970s that hungry worms no longer respond to temperature changes in their environment, but the underlying mechanisms have been unclear. I will describe unpublished work showing that insulin signaling from the gut regulates thermosensory behaviors as a function of feeding state by engaging a modulatory sensorimotor circuit that gates the output of the core thermosensory network. C. elegans is associated with, and consumes, diverse bacteria in the wild. I will also discuss a recent story in which we find that in addition to providing nutrition, a bacterial strain in the worm gut alters the hosts’ olfactory behavior and drives food choice decisions by producing a neurotransmitter that targets the hosts’ sensory neurons. These results add to our growing body of knowledge of how signaling from the gut modulates peripheral and central neuron properties and drives sensory behavioral plasticity.