anxiety

Decoding stress vulnerability

Although stress can be considered as an ongoing process that helps an organism to cope with present and future challenges, when it is too intense or uncontrollable, it can lead to adverse consequences for physical and mental health. Social stress specifically, is a highly prevalent traumatic experience, present in multiple contexts, such as war, bullying and interpersonal violence, and it has been linked with increased risk for major depression and anxiety disorders. Nevertheless, not all individuals exposed to strong stressful events develop psychopathology, with the mechanisms of resilience and vulnerability being still under investigation. During this talk, I will identify key gaps in our knowledge about stress vulnerability and I will present our recent data from our contextual fear learning protocol based on social defeat stress in mice.

Fear learning induces synaptic potentiation between engram neurons in the rat lateral amygdala

Fear learning induces synaptic potentiation between engram neurons in the rat lateral amygdala. This study by Marios Abatis et al. demonstrates how fear conditioning strengthens synaptic connections between engram cells in the lateral amygdala, revealed through optogenetic identification of neuronal ensembles and electrophysiological measurements. The work provides crucial insights into memory formation mechanisms at the synaptic level, with implications for understanding anxiety disorders and developing targeted interventions. Presented by Dr. Kenneth Hayworth, this journal club will explore the paper's methodology linking engram cell reactivation with synaptic plasticity measurements, and discuss implications for memory decoding research.

Beyond Homogeneity: Characterizing Brain Disorder Heterogeneity through EEG and Normative Modeling

Electroencephalography (EEG) has been thoroughly studied for decades in psychiatry research. Yet its integration into clinical practice as a diagnostic/prognostic tool remains unachieved. We hypothesize that a key reason is the underlying patient's heterogeneity, overlooked in psychiatric EEG research relying on a case-control approach. We combine HD-EEG with normative modeling to quantify this heterogeneity using two well-established and extensively investigated EEG characteristics -spectral power and functional connectivity- across a cohort of 1674 patients with attention-deficit/hyperactivity disorder, autism spectrum disorder, learning disorder, or anxiety, and 560 matched controls. Normative models showed that deviations from population norms among patients were highly heterogeneous and frequency-dependent. Deviation spatial overlap across patients did not exceed 40% and 24% for spectral and connectivity, respectively. Considering individual deviations in patients has significantly enhanced comparative analysis, and the identification of patient-specific markers has demonstrated a correlation with clinical assessments, representing a crucial step towards attaining precision psychiatry through EEG.

Influence of the context of administration in the antidepressant-like effects of the psychedelic 5-MeO-DMT

Psychedelics like psilocybin have shown rapid and long-lasting efficacy on depressive and anxiety symptoms. Other psychedelics with shorter half-lives, such as DMT and 5-MeO-DMT, have also shown promising preliminary outcomes in major depression, making them interesting candidates for clinical practice. Despite several promising clinical studies, the influence of the context on therapeutic responses or adverse effects remains poorly documented. To address this, we conducted preclinical studies evaluating the psychopharmacological profile of 5-MeO-DMT in contexts previously validated in mice as either pleasant (positive setting) or aversive (negative setting). Healthy C57BL/6J male mice received a single intraperitoneal (i.p.) injection of 5-MeO-DMT at doses of 0.5, 5, and 10 mg/kg, with assessments at 2 hours, 24 hours, and one week post-administration. In a corticosterone (CORT) mouse model of depression, 5-MeO-DMT was administered in different settings, and behavioral tests mimicking core symptoms of depression and anxiety were conducted. In CORT-exposed mice, an acute dose of 0.5 mg/kg administered in a neutral setting produced antidepressant-like effects at 24 hours, as observed by reduced immobility time in the Tail Suspension Test (TST). In a positive setting, the drug also reduced latency to first immobility and total immobility time in the TST. However, these beneficial effects were negated in a negative setting, where 5-MeO-DMT failed to produce antidepressant-like effects and instead elicited an anxiogenic response in the Elevated Plus Maze (EPM).Our results indicate a strong influence of setting on the psychopharmacological profile of 5-MeO-DMT. Future experiments will examine cortical markers of pre- and post-synaptic density to correlate neuroplasticity changes with the behavioral effects of 5-MeO-DMT in different settings.

Neuroestrogens as novel targets for the treatment of depression and anxiety

Brain Connectivity Workshop

Founded in 2002, the Brain Connectivity Workshop (BCW) is an annual international meeting for in-depth discussions of all aspects of brain connectivity research. By bringing together experts in computational neuroscience, neuroscience methodology and experimental neuroscience, it aims to improve the understanding of the relationship between anatomical connectivity, brain dynamics and cognitive function. These workshops have a unique format, featuring only short presentations followed by intense discussion. This year’s workshop is co-organised by Wellcome, putting the spotlight on brain connectivity in mental health disorders. We look forward to having you join us for this exciting, thought-provoking and inclusive event.

Epigenomic (re)programming of the brain and behavior by ovarian hormones

Rhythmic changes in sex hormone levels across the ovarian cycle exert powerful effects on the brain and behavior, and confer female-specific risks for neuropsychiatric conditions. In this talk, Dr. Kundakovic will discuss the role of fluctuating ovarian hormones as a critical biological factor contributing to the increased depression and anxiety risk in women. Cycling ovarian hormones drive brain and behavioral plasticity in both humans and rodents, and the talk will focus on animal studies in Dr. Kundakovic’s lab that are revealing the molecular and receptor mechanisms that underlie this female-specific brain dynamic. She will highlight the lab’s discovery of sex hormone-driven epigenetic mechanisms, namely chromatin accessibility and 3D genome changes, that dynamically regulate neuronal gene expression and brain plasticity but may also prime the (epi)genome for psychopathology. She will then describe functional studies, including hormone replacement experiments and the overexpression of an estrous cycle stage-dependent transcription factor, which provide the causal link(s) between hormone-driven chromatin dynamics and sex-specific anxiety behavior. Dr. Kundakovic will also highlight an unconventional role that chromatin dynamics may have in regulating neuronal function across the ovarian cycle, including in sex hormone-driven X chromosome plasticity and hormonally-induced epigenetic priming. In summary, these studies provide a molecular framework to understand ovarian hormone-driven brain plasticity and increased female risk for anxiety and depression, opening new avenues for sex- and gender-informed treatments for brain disorders.

Fragile minds in a scary world: trauma and post traumatic stress in very young children

Post traumatic stress disorder (PTSD) is a prevalent and disabling condition that affects larger numbers of children and adolescents worldwide. Until recently, we have understood little about the nature of PTSD reactions in our youngest children (aged under 8 years old). This talk describes our work over the last 15 years working with this very young age group. It overviews how we need a markedly different PTSD diagnosis for very young children, data on the prevalence of this new diagnostic algorithm, and the development of a psychological intervention and its evaluation in a clinical trial.

Clinical neuroscience and the heart-brain axis (BACN Mid-career Prize Lecture 2021)

Cognitive and emotional processes are shaped by the dynamic integration of brain and body. A major channel of interoceptive information comes from the heart, where phasic signals are conveyed to the brain to indicate how fast and strong the heart is beating. This talk will discuss how interoceptive processes operate across conscious and unconscious levels to influence emotion and memory. The interoceptive channel is disrupted in distinct ways in individuals with autism and anxiety. Selective interoceptive disturbance is related to symptomatology including dissociation and the transdiagnostic expression of anxiety. Interoceptive training can reduce anxiety, with enhanced interoceptive precision associated with greater insula connectivity following targeted interoceptive feedback. The discrete cardiac effects on emotion and cognition have broad relevance to clinical neuroscience, with implications for peripheral treatment targets and behavioural interventions.

Neural Representations of Social Homeostasis

How does our brain rapidly determine if something is good or bad? How do we know our place within a social group? How do we know how to behave appropriately in dynamic environments with ever-changing conditions? The Tye Lab is interested in understanding how neural circuits important for driving positive and negative motivational valence (seeking pleasure or avoiding punishment) are anatomically, genetically and functionally arranged. We study the neural mechanisms that underlie a wide range of behaviors ranging from learned to innate, including social, feeding, reward-seeking and anxiety-related behaviors. We have also become interested in “social homeostasis” -- how our brains establish a preferred set-point for social contact, and how this maintains stability within a social group. How are these circuits interconnected with one another, and how are competing mechanisms orchestrated on a neural population level? We employ optogenetic, electrophysiological, electrochemical, pharmacological and imaging approaches to probe these circuits during behavior.

Brain and behavioural impacts of early life adversity

Abuse, neglect, and other forms of uncontrollable stress during childhood and early adolescence can lead to adverse outcomes later in life, including especially perturbations in the regulation of mood and emotional states, and specifically anxiety disorders and depression. However, stress experiences vary from one individual to the next, meaning that causal relationships and mechanistic accounts are often difficult to establish in humans. This interdisciplinary talk considers the value of research in experimental animals where stressor experiences can be tightly controlled and detailed investigations of molecular, cellular, and circuit-level mechanisms can be carried out. The talk will focus on the widely used repeated maternal separation procedure in rats where rat offspring are repeatedly separated from maternal care during early postnatal life. This early life stress has remarkably persistent effects on behaviour with a general recognition that maternally-deprived animals are susceptible to depressive-like phenotypes. The validity of this conclusion will be critically appraised with convergent insights from a recent longitudinal study in maternally separated rats involving translational brain imaging, transcriptomics, and behavioural assessment.

Neuromodulation of sleep integrity

The arousal construct underlies a spectrum of behaviors that include sleep, exploration, feeding, sexual activity and adaptive stress. Pathological arousal conditions include stress, anxiety disorders, and addiction. The dynamics between arousal state transitions are modulated by norepinephrine neurons in the locus coeruleus, histaminergic neurons in the hypothalamus, dopaminergic neurons in the mesencephalon and cholinergic neurons in the basal forebrain. The hypocretin/orexin system in the lateral hypothalamus I will also present a new mechanism underlying sleep fragmentation during aging. Hcrt neurons are hyperexcitable in aged mice. We identify a potassium conductance known as the M-current, as a critical player in maintaining excitability of Hcrt neurons. Genetic disruption of KCNQ channels in Hcrt neurons of young animals results in sleep fragmentation. In contrast, treatment of aged animals with a KCNQ channel opener restores sleep/wake architecture. These data point to multiple circuits modulating sleep integrity across lifespan.

fMRI of cognitive reappraisal, acceptance, and suppression emotion regulation strategies in basic and clinically applied contexts

The ability to effectively regulate emotions is a fundamental skill related to physical and psychological health. In this talk, I will present behavioral and fMRI data from several different studies that examined cognitive reappraisal, acceptance, and suppression emotion regulation strategies in healthy controls participants and in the context of randomized trials of cognitive behavioral therapy, mindfulness- based stress reduction, and aerobic exercise as interventions for adults with anxiety disorders. We will also examine the implementation of different types of functional connectivity analytic approaches to probe intervention-related brain mechanism changes.

Apathy and Anhedonia in Adult and Adolescent Cannabis Users and Controls Before and During the COVID-19 Pandemic Lockdown

COVID-19 lockdown measures have caused severe disruptions to work and education and prevented people from engaging in many rewarding activities. Cannabis users may be especially vulnerable, having been previously shown to have higher levels of apathy and anhedonia than non-users. In this survey study, we measured apathy and anhedonia, before and after lockdown measures were implemented, in n = 256 adult and n = 200 adolescent cannabis users and n = 170 adult and n = 172 adolescent controls. Scores on the Apathy Evaluation Scale (AES) and Snaith-Hamilton Pleasure Scale (SHAPS) were investigated with mixed-measures ANCOVA, with factors user group, age group, and time, controlling for depression, anxiety, and other drug use. Adolescent cannabis users had significantly higher SHAPS scores before lockdown, indicative of greater anhedonia, compared with adolescent controls (P = .03, η p2 = .013). Contrastingly, adult users had significantly lower scores on both the SHAPS (P < .001, η p2 = .030) and AES (P < .001, η p2 = .048) after lockdown compared with adult controls. Scores on both scales increased during lockdown across groups, and this increase was significantly smaller for cannabis users (AES: P = .001, η p2 = .014; SHAPS: P = .01, η p2 = .008). Exploratory analyses revealed that dependent cannabis users had significantly higher scores overall (AES: P < .001, η p2 = .037; SHAPS: P < .001, η p2 = .029) and a larger increase in scores (AES: P = .04, η p2 =.010; SHAPS: P = .04, η p2 = .010), compared with non-dependent users. Our results suggest that adolescents and adults have differential associations between cannabis use as well as apathy and anhedonia. Within users, dependence may be associated with higher levels of apathy and anhedonia regardless of age and a greater increase in levels during the COVID-19 lockdown.

Dissecting the neural circuits underlying prefrontal regulation of reward and threat responsivity in a primate

Gaining insight into the overlapping neural circuits that regulate positive and negative emotion is an important step towards understanding the heterogeneity in the aetiology of anxiety and depression and developing new treatment targets. Determining the core contributions of the functionally heterogenous prefrontal cortex to these circuits is especially illuminating given its marked dysregulation in affective disorders. This presentation will review a series of studies in a new world monkey, the common marmoset, employing pathway-specific chemogenetics, neuroimaging, neuropharmacology and behavioural and cardiovascular analysis to dissect out prefrontal involvement in the regulation of both positive and negative emotion. Highlights will include the profound shift of sensitivity away from reward and towards threat induced by localised activations within distinct regions of vmPFC, namely areas 25 and 14 as well as the opposing contributions of this region, compared to orbitofrontal and dorsolateral prefrontal cortex, in the overall responsivity to threat. Ongoing follow-up studies are identifying the distinct downstream pathways that mediate some of these effects as well as their differential sensitivity to rapidly acting anti-depressants.

Astrocytes and oxytocin interaction regulates amygdala neuronal network activity and related behaviors”

Oxytocin orchestrates social and emotional behaviors through modulation of neural circuits in brain structures such as the central amygdala (CeA). In this structure, the release of oxytocin modulates inhibitory circuits and subsequently suppresses fear responses and decreases anxiety levels. Using astrocyte-specific gain and loss of function approaches and pharmacology, we demonstrate that oxytocin signaling in the central amygdala relies on a subpopulation of astrocytes that represent a prerequisite for proper function of CeA circuits and adequate behavioral responses, both in rats and mice. Our work identifies astrocytes as crucial cellular intermediaries of oxytocinergic modulation in emotional behaviors related to anxiety or positive reinforcement. To our knowledge, this is the first demonstration of a direct role of astrocytes in oxytocin signaling and challenges the long-held dogma that oxytocin signaling occurs exclusively via direct action on neurons in the central nervous system.

Linking valence and anxiety in a mouse insula-amygdala circuit

The influence of menstrual cycle on the indices of cortical excitability

Menstruation is a normal physiological process in women occurring as a result of changes in two ovarian produced hormones – estrogen and progesterone. As a result of these fluctuations, women experience different symptoms in their bodies – their immune system changes (Sekigawa et al, 2004), there are changes in their cardiovascular and digestive system (Millikan, 2006), as well as skin (Hall and Phillips, 2005). But these hormone fluctuations produce major changes in their behavioral pattern as well causing: anxiety, sadness, heightened irritability and anger (Severino and Moline, 1995) which is usually classified as premenstrual syndrome (PMS). In some cases these symptoms severely impair women’s lives and professional help is required. The official diagnosis according to DSM-5 (2013) is premenstrual dysphoric disorder (PMDD). Despite its ubiquitous presence the origins of PMS and PMDD are poorly understood. Some efforts to understand the underlying brain state during the menstruation cycle were performed by using TMS (Smith et al, 1999; 2002; 2003; Inghilleri et al, 2004; Hausmann et al, 2006). But all of these experiments suffer from major shortcomings - no control groups and small number of subjects. Our plan is to address all of these shortcomings and make this the biggest (to our knowledge) experiment of its kind which will, hopefully, provide us with some much needed answers.

Linking valence and anxiety in circuits of the anterior insular cortex

Information Dynamics in the Hippocampus and Cortex and their alterations in epilepsy

Neurological disorders share common high-level alterations, such as cognitive deficits, anxiety, and depression. This raises the possibility of fundamental alterations in the way information conveyed by neural firing is maintained and dispatched in the diseased brain. Using experimental epilepsy as a model of neurological disorder we tested the hypothesis of altered information processing, analyzing how neurons in the hippocampus and the entorhinal cortex store and exchange information during slow and theta oscillations. We equate the storage and sharing of information to low level, or primitive, information processing at the algorithmic level, the theoretical intermediate level between structure and function. We find that these low-level processes are organized into substates during brain states marked by theta and slow oscillations. Their internal composition and organization through time are disrupted in epilepsy, losing brain state-specificity, and shifting towards a regime of disorder in a brain region dependent manner. We propose that the alteration of information processing at an algorithmic level may be a mechanism behind the emergent and widespread co-morbidities associated with epilepsy, and perhaps other disorders.

Multi-scale synaptic analysis for psychiatric/emotional disorders

Dysregulation of emotional processing and its integration with cognitive functions are central features of many mental/emotional disorders associated both with externalizing problems (aggressive, antisocial behaviors) and internalizing problems (anxiety, depression). As Dr. Joseph LeDoux, our invited speaker of this program, wrote in his famous book “Synaptic self: How Our Brains Become Who We Are”—the brain’s synapses—are the channels through which we think, act, imagine, feel, and remember. Synapses encode the essence of personality, enabling each of us to function as a distinctive, integrated individual from moment to moment. Thus, exploring the functioning of synapses leads to the understanding of the mechanism of (patho)physiological function of our brain. In this context, we have investigated the pathophysiology of psychiatric disorders, with particular emphasis on the synaptic function of model mice of various psychiatric disorders such as schizophrenia, autism, depression, and PTSD. Our current interest is how synaptic inputs are integrated to generate the action potential. Because the spatiotemporal organization of neuronal firing is crucial for information processing, but how thousands of inputs to the dendritic spines drive the firing remains a central question in neuroscience. We identified a distinct pattern of synaptic integration in the disease-related models, in which extra-large (XL) spines generate NMDA spikes within these spines, which was sufficient to drive neuronal firing. We experimentally and theoretically observed that XL spines negatively correlated with working memory. Our work offers a whole new concept for dendritic computation and network dynamics, and the understanding of psychiatric research will be greatly reconsidered. The second half of my talk is the development of a novel synaptic tool. Because, no matter how beautifully we can illuminate the spine morphology and how accurately we can quantify the synaptic integration, the links between synapse and brain function remain correlational. In order to challenge the causal relationship between synapse and brain function, we established AS-PaRac1, which is unique not only because it can specifically label and manipulate the recently potentiated dendritic spine (Hayashi-Takagi et al, 2015, Nature). With use of AS-PaRac1, we developed an activity-dependent simultaneous labeling of the presynaptic bouton and the potentiated spines to establish “functional connectomics” in a synaptic resolution. When we apply this new imaging method for PTSD model mice, we identified a completely new functional neural circuit of brain region A→B→C with a very strong S/N in the PTSD model mice. This novel tool of “functional connectomics” and its photo-manipulation could open up new areas of emotional/psychiatric research, and by extension, shed light on the neural networks that determine who we are.

Structures in space and time - Hierarchical network dynamics in the amygdala

In addition to its role in the learning and expression of conditioned behavior, the amygdala has long been implicated in the regulation of persistent states, such as anxiety and drive. Yet, it is not evident what projections of the neuronal activity capture the functional role of the network across such different timescales, specifically when behavior and neuronal space are complex and high-dimensional. We applied a data-driven dynamical approach for the analysis of calcium imaging data from the basolateral amygdala, collected while mice performed complex, self-paced behaviors, including spatial exploration, free social interaction, and goal directed actions. The seemingly complex network dynamics was effectively described by a hierarchical, modular structure, that corresponded to behavior on multiple timescales. Our results describe the response of the network activity to perturbations along different dimensions and the interplay between slow, state-like representation and the fast processing of specific events and actions schemes. We suggest hierarchical dynamical models offer a unified framework to capture the involvement of the amygdala in transitions between persistent states underlying such different functions as sensory associative learning, action selection and emotional processing. * Work done in collaboration with Jan Gründemann, Sol Fustinana, Alejandro Tsai and Julien Courtin (@theLüthiLab)

Learning under uncertainty in autism and anxiety

Optimally interacting with a changeable and uncertain world requires estimating and representing uncertainty. Psychiatric and neurodevelopmental conditions such as anxiety and autism are characterized by an altered response to uncertainty. I will review the evidence for these phenomena from computational modelling, and outline the planned experiments from our lab to add further weight to these ideas. If time allows, I will present results from a control sample in a novel task interrogating a particular type of uncertainty and their associated transdiagnostic psychiatric traits.

Stress and the Individual: Neurobiological Mechanisms Underlying Differential Susceptibilities and Adaptations

Dr. Carmen Sandi leads the laboratory of Behavioral Genetis in EPFL, Lausanne. Her lab investigates the impact and mechanism whereby stress and anxiety affect brain and behavior in an integrative program involvong studies in rodents and humans. She is the founder and co-president of Swiss Stress Network, co-director of Swiss National Centre of Competence in Research Synapsy. She is Chair of the ALBA Network, and pas-President of Cajal Advanced Neuroscience Training Program and the Federation of European Neuroscience Societies.

How Brain Circuits Function in Health and Disease: Understanding Brain-wide Current Flow

Dr. Rajan and her lab design neural network models based on experimental data, and reverse-engineer them to figure out how brain circuits function in health and disease. They recently developed a powerful framework for tracing neural paths across multiple brain regions— called Current-Based Decomposition (CURBD). This new approach enables the computation of excitatory and inhibitory input currents that drive a given neuron, aiding in the discovery of how entire populations of neurons behave across multiple interacting brain regions. Dr. Rajan’s team has applied this method to studying the neural underpinnings of behavior. As an example, when CURBD was applied to data gathered from an animal model often used to study depression- and anxiety-like behaviors (i.e., learned helplessness) the underlying biology driving adaptive and maladaptive behaviors in the face of stress was revealed. With this framework Dr. Rajan's team probes for mechanisms at work across brain regions that support both healthy and disease states-- as well as identify key divergences from multiple different nervous systems, including zebrafish, mice, non-human primates, and humans.

Organization of Midbrain Serotonin System

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.

The role of orexin/hypocretin in social behaviour

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.

Blurring the boundaries between neuroscience and organismal physiology

Work in my laboratory is based on the assumptions that we do not know yet how all physiological functions are regulated and that mouse genetics by allowing to identify novel inter-organ communications is the most efficient ways to identify novel regulation of physiological functions. We test these two contention through the study of bone which is the organ my lab has studied since its inception. Based on precise cell biological and clinical reasons that will be presented during the seminar we hypothesized that bone should be a regulator of energy metabolism and reproduction and identified a bone-derived hormone termed osteocalcin that is responsible of these regulatory events. The study of this hormone revealed that in addition to its predicted functions it also regulates brain size, hippocampus development, prevents anxiety and depression and favors spatial learning and memory by signaling through a specific receptor we characterized. As will be presented, we elucidated some of the molecular events accounting for the influence of osteocalcin on brain and showed that maternal osteocalcin is the pool of this hormone that affects brain development. Subsequently and looking at all the physiological functions regulated by osteocalcin, i.e., memory, the ability to exercise, glucose metabolism, the regulation of testosterone biosynthesis, we realized that are all need or regulated in the case of danger. In other words it suggested that osteocalcin is an hormone needed to sense and overcome acute danger. Consonant with this hypothesis we next showed this led us to demonstrate that bone via osteocalcin is needed to mount an acute stress response through molecular and cellular mechanisms that will be presented during the seminar. overall, an evolutionary appraisal of bone biology, this body of work and experiments ongoing in the lab concur to suggest 1] the appearance of bone during evolution has changed how physiological functions as diverse as memory, the acute stress response but also exercise and glucose metabolism are regulated and 2] identified bone and osteocalcin as its molecular vector, as an organ needed to sense and response to danger.

Investigating the impact of the pandemic on adolescent anxiety and cognitive function

Meg was awarded funding to look into how the coronavirus pandemic has affected children's mental health and wellbeing.

Ex vivo gene therapy for epilepsy. Seizure-suppressant and neuroprotective effects of encapsulated GDNF-producing cells

A variety of pharmacological treatments exist for patients suffering from focal seizures, but systemically administered drugs offer only symptomatic relief and frequently cause unwanted side effects. Moreover, available drugs are ineffective in one third of the patients. Thus, developing more targeted and effective treatment strategies is highly warranted. Neurotrophic factors are candidates for treating epilepsy, but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the brain. We have developed an implantable cell encapsulation system that delivers high and consistent levels of neurotrophic molecules directly to a specific brain region. The potential of this approach has been tested by delivering glial cell line-derived neurotrophic factor (GDNF) to the hippocampus of epileptic rats. In vivo studies demonstrated that these intrahippocampal implants continue to secrete GDNF and produce high hippocampal GDNF tissue levels in a long-lasting manner. Identical implants rapidly and greatly reduced seizure frequency in the pilocarpine model. This effect increased in magnitude over 3 months, ultimately leading to a reduction of spontaneous seizures by more than 90%. Importantly, these effects were accompanied by improvements in cognition and anxiety, and by the normalization of many histological alterations that are associated with chronic epilepsy. In addition, the antiseizure effect persisted even after device removal. Finally, by establishing a unilateral epileptic focus using the intrahippocampal kainate model, we found that delivery of GDNF exclusively within the focus suppressed already established spontaneous recurrent seizures. Together, these results support the concept that the implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner. These findings may form the basis for clinical translation of this approach.

Analogies, Games and the Learning of Mathematics

Research on analogical processing and reasoning has provided strong evidence that the use of adequate educational analogies has strong and positive effects on the learning of mathematics. In this talk I will show some experimental results suggesting that analogies based on spatial representations might be particularly effective to improve mathematics learning. Since fostering mathematics learning also involves addressing psychosocial factors such as the development of mathematical anxiety, providing social incentives to learn, and fostering engagement and motivation, I will argue that one area to explore with great potential to improve math learning is applying analogical research in the development of learning games aimed to improve math learning. Finally, I will show some early prototypes of an educational project devoted to developing games designed to foster the learning of early mathematics in kindergarten children.

Neurotoxicity is a major health problem in Africa: focus on Parkinson's / Parkinsonism

Parkinson's disease (PD) is the second most present neurodegenerative disease in the world after Alzheimer's. It is due to the progressive and irreversible loss of dopaminergic neurons of the substantia nigra Pars Compacta. Alpha synuclein deposits and the appearance of Lewi bodies are systematically associated with it. PD is characterized by four cardinal motor symptoms: bradykinesia / akinesia, rigidity, postural instability and tremors at rest. These symptoms appear when 80% of the dopaminergic endings disappear in the striatum. According to Braak's theory, non-motor symptoms appear much earlier and this is particularly the case with anxiety, depression, anhedonia, and sleep disturbances. In 90 to 95% of cases, the causes of the appearance of the disease remain unknown, but polluting toxic molecules are incriminated more and more. In Africa, neurodegenerative diseases of the Parkinson's type are increasingly present and a parallel seems to exist between the increase in cases and the presence of toxic and polluting products such as metals. My Web conference will focus on this aspect, i.e. present experimental arguments which reinforce the hypothesis of the incrimination of these pollutants in the incidence of Parkinson's disease and / or Parkinsonism. Among the lines of research that we have developed in my laboratory in Rabat, Morocco, I have chosen this one knowing that many of our PhD students and IBRO Alumni are working or trying to develop scientific research on neurotoxicity in correlation with pathologies of the brain.

Neurological consequences of COVID-19

The speakers will outline how neurologists in Bristol have been research-active during the COVID-19 pandemic including our contribution to national and international surveillance programmes as well as initiating research studies such as an evaluation of the impact of COVID anxiety on sleep and neurodegeneration and determining whether vascular changes in the eye predict COVID-19 severity.

Neural Circuit Mechanisms of Emotional and Social Processing

How does our brain rapidly determine if something is good or bad? How do we know our place within a social group? How do we know how to behave appropriately in dynamic environments with ever-changing conditions? The Tye Lab is interested in understanding how neural circuits important for driving positive and negative motivational valence (seeking pleasure or avoiding punishment) are anatomically, genetically and functionally arranged. We study the neural mechanisms that underlie a wide range of behaviours ranging from learned to innate, including social, feeding, reward-seeking and anxiety-related behaviours. We have also become interested in “social homeostasis” -- how our brains establish a preferred set-point for social contact, and how this maintains stability within a social group. How are these circuits interconnected with one another, and how are competing mechanisms orchestrated on a neural population level? We employ optogenetic, electrophysiological, electrochemical, pharmacological and imaging approaches to probe these circuits during behaviour.

Anticipatory coding of anxiety in the ventral hippocampus

Anxiety levels after vicarious social defeat stress are associated with vulnerability and resilience to cocaine-induced conditioned place preference in female mice

Anxiety and social-like deficits in Alzheimer’s disease in the TgF344-AD rat

Anxiety-like behavior in adolescent mice prenatally exposed to different doses of levetiracetam

Assessing neural activity of musicians with music performance anxiety: Creation and validation of the fMRI Social-Evaluative Music Performance Task

Binge-eating alters dopaminergic system, reduces anxiety, and increases impulsivity in periadolescent rats

Blood brain barrier differences in the nucleus accumbens relate to natural variation in trait anxiety

Blood-circulating lipids regulate adult hippocampal neurogenesis in the context of anxiety

BRAF hyperactivating mutation in forebrain GABAergic interneurons increases anxiety and impairs working memory in mice

Cell-type-specific dopamine signaling in ventral hippocampus tracks anxiety

Comparing efficacy of SSRIs to ameliorate anxiety-like behaviour induced either by ventromedial prefrontal overactivation or occurring naturally in trait-anxious marmosets

Contribution of GirK channels expressed in VTA GABAergic neurons to anxiety, social behaviors and hippocampal-dependent memory

Correlations between the white matter anisotropy at the whole-brain scale and anxiety ratings

CRH-ergic neurons of median raphe region regulate stress and anxiety

Deletion of beta2 nicotinic subunit in specific types of cortical GABAergic neurons changes social and anxiety-like behavior

Dlx5/6 levels in mouse GABAergic neurons affect adult Parvalbumin-positive neuronal density and control anxiety/compulsive behaviours

Early-onset and late-onset calorie restriction differently modulate anxiety-like behavior in aging female Wistar rats

Effects of L-Dopa, SKF-38393, and Quinpirole on exploratory, anxiety- and depressive-like behaviors in pubertal female and male mice

Effects of a psychedelic 5-HT2A receptor agonist on anxiety-related behavior and fear processing in mice

Enriched environment attenuates enhanced trait-anxiety and associated neuro-inflammatory dysbalance

Excessive midbrain glutamatergic tone promote anxiety via dysregulation of amygdala principal neurons

Focus on the mouse insular cortex: in vivo single-unit recordings during anxiety assays and mapping of the dopaminergic system

Foraging under threat and its relationship to real-life anxiety

Functional dissociation of ventral hippocampal inhibitory circuits during anxiety and fear behaviors

Gating of hunger and anxiety signaling through NPY-dependent synaptic plasticity in the BNST

Harnessing the heterogeneity of freezing responses in mice to understand biological bases of spectrum of anxiety disorders

Human metabotropic glutamate receptor 5 (mGluR5) antibodies induce memory loss, increased anxiety and molecular changes in mice

Impact of odor-induced reduction in anxiety on brain’s activity and connectivity

Implication of the VIP/VPAC1/2 system in the regulation of stress and anxiety reactions in rodents

The influence of childhood trauma and epigenetic variation in OXTR on anxiety proneness and structural neuroimaging measures in a South African adolescent cohort

Kisspeptin-13 may induce anxiety-like behaviour via modulation of central vasopressin in rats

Linking emotional valence and anxiety in a mouse insula-amygdala circuit

Loss of MCT4 in microglia results in altered brain development and anxiety-like behavior

Mitochondria, adult hippocampal neurogenesis, and anxiety

Nicotine effects on anxiety behavior and brain biochemical markers in adult male mice and in rat hippocampal slices: patch clamp recordings

A novel approach to measure individual traits reveals a plasticity-focused genetic profile of anxiety

Physiological, neuronal and pharmacological identification of panic and anxiety-like states during freezing

A preclinical model of comorbid anxiety and depression

A primate subcallosal cingulate area 25 network fractionates anhedonia, anxiety and rapid antidepressant response

Dopamine controls neural coding of anxiety and valence in the mouse anterior insula

COSYNE 2025