Neuroscience seminars

Team work makes sensory streams work: our senses work together, learn from each other, and stand in for one another, the result of which is perception and understanding. Learned associations between stimuli in different sensory modalities can shape the way we perceive these stimuli (Mcgurk and Macdonald, 1976). During audio-visual associative learning, auditory cortex is thought to underlie multi-modal plasticity in visual cortex (McIntosh et al., 1998; Mishra et al., 2007; Zangenehpour and Zatorre, 2010). However, it is not well understood how processing in visual cortex is altered by an auditory stimulus that is predictive of a visual stimulus and what the mechanisms are that mediate such experience-dependent, audio-visual associations in sensory cortex. Here we describe a neural mechanism by which an auditory input can shape visual representations of behaviorally relevant stimuli through direct interactions between auditory and visual cortices. We show that the association of an auditory stimulus with a visual stimulus in a behaviorally relevant context leads to an experience-dependent suppression of visual responses in primary visual cortex (V1). Auditory cortex axons carry a mixture of auditory and retinotopically-matched visual input to V1, and optogenetic stimulation of these axons selectively suppresses V1 neurons responsive to the associated visual stimulus after, but not before, learning. Our results suggest that cross-modal associations can be stored in long-range cortical connections and that with learning these cross-modal connections function to suppress the responses to predictable input.

The ability to experience pain is old in evolutionary terms. It is an experience shared across species. Acute pain is the body’s alarm system, and as such it is a good thing. Pain that persists beyond normal tissue healing time (3-4 months) is defined as chronic – it is the system gone wrong and it is not a good thing. Chronic pain has recently been classified as both a symptom and disease in its own right. It is one of the largest medical health problems worldwide with one in five adults diagnosed with the condition. The brain is key to the experience of pain and pain relief. This is the place where pain emerges as a perception. So, relating specific brain measures using advanced neuroimaging to the change patients describe in their pain perception induced by peripheral or central sensitization (i.e. amplification), psychological or pharmacological mechanisms has tremendous value. Identifying where amplification or attenuation processes occur along the journey from injury to the brain (i.e. peripheral nerves, spinal cord, brainstem and brain) for an individual and relating these neural mechanisms to specific pain experiences, measures of pain relief, persistence of pain states, degree of injury and the subject's underlying genetics, has neuroscientific and potential diagnostic relevance. This is what neuroimaging has afforded – a better understanding and explanation of why someone’s pain is the way it is. We can go ‘behind the scenes’ of the subjective report to find out what key changes and mechanisms make up an individual’s particular pain experience. A key area of development has been pharmacological imaging where objective evidence of drugs reaching the target and working can be obtained. We even now understand the mechanisms of placebo analgesia – a powerful phenomenon known about for millennia. More recently, researchers have been investigating through brain imaging whether there is a pre-disposing vulnerability in brain networks towards developing chronic pain. So, advanced neuroimaging studies can powerfully aid explanation of a subject’s multidimensional pain experience, pain relief (analgesia) and even what makes them vulnerable to developing chronic pain. The application of this goes beyond the clinic and has relevance in courts of law, and other areas of society, such as in veterinary care. Relatively far less work has been directed at understanding what changes in the brain occur during altered states of consciousness induced either endogenously (e.g. sleep) or exogenously (e.g. anaesthesia). However, that situation is changing rapidly. Our recent multimodal neuroimaging work explores how anaesthetic agents produce altered states of consciousness such that perceptual experiences of pain and awareness are degraded. This is bringing us fascinating insights into the complex phenomenon of anaesthesia, consciousness and even the concept of self-hood. These topics will be discussed in my talk alongside my ‘side-story’ of life as a scientist combining academic leadership roles with doing science and raising a family.

Studies of neural circuit plasticity focus almost exclusively on functional and structural changes of neuronal synapses. In recent years, however, myelin plasticity has emerged as a potential modulator of neuronal networks. Myelination of previously unmyelinated axons and changes in the structure on already-myelinated axons can have large effects on the function of neuronal networks. Yet myelination has been mostly studied in relation to its functional and metabolic activity. Myelin modifications are increasingly being implicated as a mechanism for sensory-motor learning and unpublished data from our lab indicate that myelination also occurs during cognitive non-motor learning. It is, however, unclear how specific these myelin changes are and even less is known of the underlying mechanisms of learning-evoked myelin plasticity. In this journal club, Dr Giulia Bonetto will provide a general overview on myelin plasticity. Additionally, she will present new data addressing the role of myelin plasticity in cognitive non-motor learning.

Rhythmic activity in the brain has been reported in relation to a wide range of cognitive processes. Changes in the rhythmic activity have been related to pathological states. These observations raise the question of the origin of these rhythms: can the mechanisms responsible for generation of these rhythms and that allow the propagation of the rhythmic signal be acquired via a process of learning? In my talk I will focus on spike timing dependent plasticity (STDP) and examine under what conditions this unsupervised learning rule can facilitate the propagation of rhythmic activity downstream in the central nervous system. Next, the I will apply the theory of STDP to the whisker system and demonstrate how STDP can shape the distribution of preferred phases of firing in a downstream population. Interestingly, in both these cases STDP dynamics does not relax to a fixed-point solution, rather the synaptic weights remain dynamic. Nevertheless, STDP allows for the system to retain its functionality in the face of continuous remodeling of the entire synaptic population.

There are no effective disease-modifying therapies for neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis or Huntington’s disease. Huntington’s disease (HD) is a devastating autosomal dominantly inherited neurodegenerative disease and the world’s most common genetic dementia. I will present an overview of important approaches in development for targeting mutant HTT DNA and RNA (Tabrizi et al Neuron 2019), the cause of HD pathogenesis, and the translational pathway from bench to clinic for a HTT targeting antisense oligonucleotide (Tabrizi et al New England Journal of Medicine 2019, Tabrizi, Science 2020) which is now in phase 3 studies. In my talk I will also review some of the genetic approaches in development for other CNS diseases. I will talk a bit about my journey as a clinician scientist and share some of my learnings for young scientists on how to survive a career in science.

The serotonin system is the most frequently targeted neural system pharmacologically for treating psychiatric disorders, including depression and anxiety. Serotonin neurons of the dorsal and median raphe nuclei (DR, MR) collectively innervate the entire forebrain and midbrain, modulating diverse physiology and behaviour. By using viral-genetic methods, we found that DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioural functions. To gain a fundamental understanding of the molecular heterogeneity of DR and MR, we used single-cell RNA - sequencing (scRNA-seq) to generate a comprehensive dataset comprising eleven transcriptomically distinct serotonin neuron clusters. We generated novel intersectional viral-genetic tools to access specific subpopulations. Whole-brain axonal projection mapping revealed that the molecular features of these distinct serotonin groups reflect their anatomical organization and provide tools for future exploration of the full projection map of molecularly defined serotonin groups. The molecular architecture of serotonin system lays the foundation for integrating anatomical, neurochemical, physiological, and behavioural functions.

I will discuss the mechanisms that determine whether a weak visual stimulus will reach consciousness or not. If the stimulus is simple, early visual cortex acts as a relay station that sends the information to higher visual areas. If the stimulus arrives at a minimal strength, it will be stored in working memory. However, during more complex visual perceptions, which for example depend on the segregation of a figure from the background, early visual cortex’ role goes beyond a simply relay. It now acts as a cognitive blackboard and conscious perception depends on it. Our results also inspire new approaches to create a visual prosthesis for the blind, by creating a direct interface with the visual cortex. I will discuss how high-channel-number interfaces with the visual cortex might be used to restore a rudimentary form of vision in blind individuals.

The NeurotechEU student councils invites you to a special event on the occasion of the International Women's Day. 15 different speakers from very different backgrounds, seniority and expertise will share their experience on women in science, from students, to professeurs, to researchers, to the European Commission, discover their very unique insights.

My lab is focused on how brain encodes and modulates social interactions. Intraspecific social interactions are integral for survival and maintenance of society among all mammalian species. Despite the importance of social interactions, we lack a complete understanding of the brain circuitry involved in processing social behaviour. My lab investigates how the hypothalamic orexin (hypocretin) neurons and their downstream circuits participate in social interaction behaviours. These neurons are located exclusively in the hypothalamus that regulates complex and goal-directed behaviours. We recently identified that orexin neurons differentially encode interaction between familiar and novel animals. We are currently investigating how chronic social isolation, a risk factor for the development of social-anxiety like behaviours, affects orexin neuron activity and how we can manipulate the activity of these neurons to mitigate isolation-induced social deficits.

The COINTOB (conditional intention and integration to bound) model provides a heuristic framework of processes in Libet-style experiments. The model is based on three assumptions. First, brain activation preceding conscious intentions in Libet-style experiments does not reflect an unconscious decision but rather the unfolding of a decision process. Second, the time of conscious decision (W) reflects the moment in time when the decision boundary is crossed. This interpretation of W is consistent with our apparent intuition that we decide in the moment we experience the conscious intention to act. Third, the decision process is configured by conscious intentions that participants form at the beginning of the experiment based on the experimental instruction. Brass and Mele discuss the model, conceptual background for it, and the model’s bearing on free will.

During learning, populations of neurons alter their connectivity and activity patterns, enabling the brain to construct a model of the external world. Conventional wisdom holds that the durability of a such a model is reflected in the stability of neural responses and the stability of synaptic connections that form memory engrams. However, recent experimental findings have challenged this idea, revealing that neural population activity in circuits involved in sensory perception, motor planning and spatial memory continually change over time during familiar behavioural tasks. This continual change suggests significant redundancy in neural representations, with many circuit configurations providing equivalent function. I will describe recent work that explores the consequences of such redundancy for learning and for task representation. Despite large changes in neural activity, we find cortical responses in sensorimotor tasks admit a relatively stable readout at the population level. Furthermore, we find that redundancy in circuit connectivity can make a task easier to learn and compensate for deficiencies in biological learning rules. Finally, if neuronal connections are subject to an unavoidable level of turnover, the level of plasticity required to optimally maintain a memory is generally lower than the total change due to turnover itself, predicting continual reconfiguration of an engram.

We want to understand how the visual system detects and tracks salient stimuli in the environment to initiate and guide specific behaviors (i.e., visual neuroethology). Predator avoidance and prey capture are central selection pressures of animal evolution. Mice use vision to detect aerial predators and hunt insects. I will discuss studies from my group that identify specific circuits and pathways in the early visual system (i.e., the retina and its subcortical targets) mediating predator avoidance and prey capture in mice. Our results highlight the importance of subcellular visual processing in the retina and the alignment of viewing strategies with region- and cell-type-specific retinal ganglion cell projection patterns to the brain.

In many learning and decision scenarios, especially sequential settings like mazes or games, it is easy to state an objective function but difficult to compute it, for instance because this can require enumerating many possible future trajectories. This, in turn, motivates a variety of more tractable approximations which then raise resource-rationality questions about whether and when an efficient agent should invest time or resources in computing decision variables more accurately. Previous work has used a simple all-or-nothing version of this reasoning as a framework to explain many phenomena of automaticity, habits, and compulsion in humans and animals. Here, I present a more finegrained theoretical analysis of deliberation, which attempts to address not just whether to deliberate vs. act, but which of many possible actions and trajectories to consider. Empirically, I first motivate and compare this account to nonlocal representations of spatial trajectories in the rodent place cell system, which are thought to be involved in planning. I also consider its implications, in humans, for variation over time and situations in subjective feelings of mental effort, boredom, and cognitive fatigue. Finally, I present results from a new study using magnetoencephalography in humans to measure subjective consideration of possible trajectories during a sequential learning task, and study its relationship to rational prioritization and to choice behavior.

Distinct synapses influence one another when they undergo changes, with unclear consequences for neuronal dynamics and function. Here we show that synapses can interact such that excitatory currents are naturally normalised and balanced by inhibitory inputs. This happens when classical spike-timing dependent synaptic plasticity rules are extended by additional mechanisms that incorporate the influence of neighbouring synaptic currents and regulate the amplitude of efficacy changes accordingly. The resulting control of excitatory plasticity by inhibitory activation, and vice versa, gives rise to quick and long-lasting memories as seen experimentally in receptive field plasticity paradigms. In models with additional dendritic structure, we observe experimentally reported clustering of co-active synapses that depends on initial connectivity and morphology. Finally, in recurrent neural networks, rich and stable dynamics with high input sensitivity emerge, providing transient activity that resembles recordings from the motor cortex. Our model provides a general framework for codependent plasticity that frames individual synaptic modifications in the context of population-wide changes, allowing us to connect micro-level physiology with behavioural phenomena.

Regulation of information flow in the brain is critical for many forms of behavior. In the process of sensory based decision-making, decisions about future actions are held in memory until enacted, making them potentially vulnerable to distracting sensory input. Therefore, gating of information flow from sensory to motor areas could protect memory from interference during decision-making, but the underlying network mechanisms are not understood. I will present our recent experimental and modeling work describing how information flow from the sensory cortex can be gated by state-dependent frontal cortex dynamics during decision-making in mice. Our results show that communication between brain regions can be regulated via attractor dynamics, which control the degree of commitment to an action, and reveal a novel mechanism of gating of neural information.

Dravet syndrome (DS) is a neurodevelopmental disorder caused by heterozygous loss-of-function of the gene SCN1A encoding the voltage-gated sodium channel subunit Nav1.1, and is defined by treatment-resistant epilepsy, intellectual impairment, and sudden death. However, disease mechanisms remain unclear, as previously-identified deficiency in action potential generation of Nav1.1-expressing parvalbumin-positive fast-spiking GABAergic interneurons (PV-INs) in DS (Scn1a+/-) mice normalizes during development. We used a novel approach that facilitated the assessment of PV-IN function at both early (post-natal day (P) 16-21) and late (P35-56) time points in the same mice. We confirmed that PV-IN spike generation was impaired at P16-21 in all mice (those deceased from SUDEP by P35 and those surviving to P35-56). However, unitary synaptic transmission assessed in PV-IN:principal cell paired recordings was severely dysfunctional selectively in mice recorded at P16-21 that did not survive to P35. Spike generation in surviving mice had normalized by P35-56; yet we again identified abnormalities in synaptic transmission in surviving mice. We propose that early dysfunction of PV-IN spike propagation drives epilepsy severity and risk of sudden death, while persistent dysfunction of spike propagation contributes to chronic DS pathology.