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.

Unlike traditional monoamine-based antidepressants that require weeks to exert effects, ketamine alleviates depression within hours, though its clinical use is limited by side effects. While ketamine was initially thought to work primarily through NMDA receptor (NMDAR) inhibition, our research reveals a more complex mechanism. We demonstrate that NMDAR inhibition alone cannot explain ketamine's sustained antidepressant effects, as other NMDAR antagonists like MK-801 lack similar efficacy. Instead, the (2R,6R)-hydroxynorketamine (HNK) metabolite appears critical, exhibiting antidepressant effects without ketamine's side effects. Paradoxically, our findings suggest an inverted U-shaped dose-response relationship where excessive NMDAR inhibition may actually impede antidepressant efficacy, while some level of NMDAR activation is necessary. The antidepressant actions of ketamine and (2R,6R)-HNK require AMPA receptor activation, leading to synaptic potentiation and upregulation of AMPA receptor subunits GluA1 and GluA2. Furthermore, NMDAR subunit GluN2A appears necessary and possibly sufficient for these effects. This research establishes NMDAR-GluN2A activation as a common downstream effector for rapid-acting antidepressants, regardless of their initial targets, offering promising directions for developing next-generation antidepressants with improved efficacy and reduced side effects.

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.

In April, we will host Nolan Williams and Mustafa Husain. Be prepared to embark on a journey from early brain stimulation with ECT to state-of-the art TMS protocols and magnetic seizure therapy! The talks will be held on Thursday, April 25th at noon ET / 6PM CET. Nolan Williams, MD, is an associate professor of Psychiatry and Behavioral Science at Stanford University. He developed the SAINT protocol, which is the first FDA-cleared non-invasive, rapid-acting neuromodulation treatment for treatment-resistant depression. Mustafa Husain, MD, is an adjunct professor of Psychiatry and Behavioral Sciences at Duke University and a professor of Psychiatry and Neurology at UT Southwestern Medical Center, Dallas. He will tell us about “Evolution of convulsive therapy from electroconvulsive therapy to Magnetic Seizure Therapy”. As always, we will also get a glimpse at the “Person behind the science”. Please register va talks.stimulatingbrains.org to receive the (free) Zoom link, subscribe to our newsletter, or follow us on Twitter/X for further updates!

A core aspect of clinical epileptology revolves around relating epileptic field potentials to underlying neural sources (e.g. an “epileptogenic focus”). Yet still, how neural population activity relates to epileptic field potentials and ultimately clinical phenomenology, remains far from being understood. After a brief overview on this topic, this seminar will focus on unpublished work, with an emphasis on seizure-related focal spreading depression. The presented results will include hippocampal and neocortical chronic in vivo two-photon population imaging and local field potential recordings of epileptic micronetworks in mice, in the context of viral encephalitis or optogenetic stimulation. The findings are corroborated by invasive depth electrode recordings (macroelectrodes and BF microwires) in epilepsy patients during pre-surgical evaluation. The presented work carries general implications for clinical epileptology, and basic epilepsy research.

The use of molecular imaging, particularly PET and SPECT, has significantly transformed the treatment of schizophrenia with antipsychotic drugs since the late 1980s. It has offered insights into the links between drug target engagement, clinical effects, and side effects. A therapeutic window for receptor occupancy is established for antipsychotics, yet there is a divergence of opinions regarding the importance of blood levels, with many downplaying their significance. As a result, the role of therapeutic drug monitoring (TDM) as a personalized therapy tool is often underrated. Since molecular imaging of antipsychotics has focused almost entirely on D2-like dopamine receptors and their potential to control positive symptoms, negative symptoms and cognitive deficits are hardly or not at all investigated. Alternative methods have been introduced, i.e. to investigate the correlation between approximated receptor occupancies from blood levels and cognitive measures. Within the domain of antidepressants, and specifically regarding ketamine's efficacy in depression treatment, there is limited comprehension of the association between plasma concentrations and target engagement. The measurement of AMPA receptors in the human brain has added a new level of comprehension regarding ketamine's antidepressant effects. To ensure precise prescription of psychotropic drugs, it is vital to have a nuanced understanding of how molecular and clinical effects interact. Clinician scientists are assigned with the task of integrating these indispensable pharmacological insights into practice, thereby ensuring a rational and effective approach to the treatment of mental health disorders, signaling a new era of personalized drug therapy mechanisms that promote neuronal plasticity not only under pathological conditions, but also in the healthy aging brain.

Web-based self-help interventions for coping with prolonged grief have established their efficacy. However, few programs address recent losses and investigate the effect of self-tailoring of the content. In an international project, the text-based self-help program LIVIA was adapted and complemented with an Embodied Conversational Agent, an initial risk assessment and a monitoring tool. The new program SOLENA was evaluated in three trials in Switzerland, the Netherlands and Portugal. The aim of the trials was to evaluate the clinical efficacy for reducing grief, depression and loneliness and to examine client satisfaction and technology acceptance. The talk will present the SOLENA program and report results of the Portuguese and Dutch trial as well as preliminary results of the Swiss RCT. The ongoing Swiss trial compares a standardised to a self-tailored delivery format and analyses clinical outcomes, the helpfulness of specific content and the working alliance. Finally, lessons learned in the development and evaluation of a web-based self-help intervention for older adults will be discusses.

Sleep strongly affects synaptic strength, making it critical for cognition, especially learning and memory formation. Whether and how sleep deprivation modulates human brain physiology and cognition is poorly understood. Here we examined how overnight sleep deprivation vs overnight sufficient sleep affects (a) cortical excitability, measured by transcranial magnetic stimulation, (b) inducibility of long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity via transcranial direct current stimulation (tDCS), and (c) learning, memory, and attention. We found that sleep deprivation increases cortical excitability due to enhanced glutamate-related cortical facilitation and decreases and/or reverses GABAergic cortical inhibition. Furthermore, tDCS-induced LTP-like plasticity (anodal) abolishes while the inhibitory LTD-like plasticity (cathodal) converts to excitatory LTP-like plasticity under sleep deprivation. This is associated with increased EEG theta oscillations due to sleep pressure. Motor learning, behavioral counterparts of plasticity, and working memory and attention, which rely on cortical excitability, are also impaired during sleep deprivation. Our study indicates that upscaled brain excitability and altered plasticity, due to sleep deprivation, are associated with impaired cognitive performance. Besides showing how brain physiology and cognition undergo changes (from neurophysiology to higher-order cognition) under sleep pressure, the findings have implications for variability and optimal application of noninvasive brain stimulation.

Emotions and social interactions color our lives and shape our behaviors. Using animal models and engineered manipulations, we aim to understand how social and emotional behaviors are encoded in the brain, focusing on the neural circuits underlying dominance hierarchy and depression. This lecture will highlight our recent discoveries on how downward social mobility leads to depression; how ketamine tames depression by blocking burst firing in the brain’s antireward center; and, how glia-neuron interaction plays a surprising role in this process. I will also present our recent work on the mechanism underlying the sustained antidepressant activity of ketamine and its brain region specificity. With these results, we hope to illuminate on a more unified theory on ketamine’s mode of action and inspire new treatment strategies for depression.

Emotions and social interactions color our lives and shape our behaviors. Using animal models and engineered manipulations, we aim to understand how social and emotional behaviors are encoded in the brain, focusing on the neural circuits underlying dominance hierarchy and depression. This lecture will highlight our recent discoveries on how downward social mobility leads to depression; how ketamine tames depression by blocking burst firing in the brain’s antireward center; and, how glia-neuron interaction plays a surprising role in this process. I will also present our recent work on the mechanism underlying the sustained antidepressant activity of ketamine and its brain region specificity. With these results, we hope to illuminate on a more unified theory on ketamine’s mode of action and inspire new treatment strategies for depression.

Critical phenomena abound in nature, from forest fires and earthquakes to avalanches in sand and neuronal activity. Since the 2003 publication by Beggs & Plenz on neuronal avalanches, a growing body of work suggests that the brain homeostatically regulates itself to operate near a critical point where information processing is optimal. At this critical point, incoming activity is neither amplified (supercritical) nor damped (subcritical), but approximately preserved as it passes through neural networks. Departures from the critical point have been associated with conditions of poor neurological health like epilepsy, Alzheimer's disease, and depression. One complication that arises from this picture is that the critical point assumes no external input. But, biological neural networks are constantly bombarded by external input. How is then the brain able to homeostatically adapt near the critical point? We’ll see that the theory of quasicriticality, an organizing principle for brain dynamics, can account for this paradoxical situation. As external stimuli drive the cortex, quasicriticality predicts a departure from criticality while maintaining optimal properties for information transmission. We’ll see that simulations and experimental data confirm these predictions and describe new ones that could be tested soon. More importantly, we will see how this organizing principle could help in the search for biomarkers that could soon be tested in clinical studies.

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.

Although bradykinesia, tremor, and rigidity are hallmark motor defects in Parkinson’s disease (PD) patients, they also experience motor learning impairments and non-motor symptoms such as depression. The neural basis for these different PD symptoms are not well understood. While current treatments are effective for locomotion deficits in PD, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking. We found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN), and nucleus accumbens (NAc). While PF-->CPu and PF-->STN circuits are critical for locomotion and motor learning respectively, inhibition of the PF-->NAc circuit induced a depression-like state. While chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation at PF-->STN synapses restored motor learning behavior in PD model mice. Furthermore, activation of NAc-projecting PF neurons rescued depression-like PD phenotypes. Importantly, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.

Face detection is an initial step of many social interactions involving a comparison between a visual input and a mental representation of faces, built from previous experience. Whilst emotional state was found to affect the way humans attend to faces, little research has explored the effects of emotions on the mental representation of faces. Here, we examined the specific perceptual modulation of geometric properties of the mental representations associated with state anxiety and state depression on face detection, and to compare their emotional expression. To this end, we used an adaptation of the reverse correlation technique inspired by Gosselin and Schyns’, (2003) ‘Superstitious Approach’, to construct visual representations of observers’ mental representations of faces and to relate these to their mental states. In two sessions, on separate days, participants were presented with ‘colourful’ noise stimuli and asked to detect faces, which they were told were present. Based on the noise fragments that were identified as faces, we reconstructed the pictorial mental representation utilised by each participant in each session. We found a significant correlation between the size of the mental representation of faces and participants’ level of depression. Our findings provide a preliminary insight about the way emotions affect appearance expectation of faces. To further understand whether the facial expressions of participants’ mental representations reflect their emotional state, we are conducting a validation study with a group of naïve observers who are asked to classify the reconstructed face images by emotion. Thus, we assess whether the faces communicate participants’ emotional states to others.

My research focuses broadly on the lifelong health disparities associated with experiences of adversity early in life. In this talk I will present the results of our recently completed Teen Resilience Project, a prospective and longitudinal study of first onset depression during adolescence. First, I will present the results on whether and how inflammatory processes may be shaped by early life adversity. Second, I will present data on the role of stress-induced inflammation in reward-related psychological processes. Finally, I will discuss the biobehavioral predictors of first-onset depression in this sample.

Development of new medications for mental health conditions is a pressing need given the high proportion of people not responding to available treatments. We hope that presenting ebselen to a wider audience will inspire further studies on this promising agent with a benign side-effects profile. Laboratory research, animal research and human studies suggest that ebselen shares many features with the mood stabilising drug lithium, creating a promise of a drug that would have a similar clinical effect but without lithium’s troublesome side-effect profile and toxicity. Both drugs have a common biological target, inositol monophosphatase, whose inhibition is thought key to lithium’s therapeutic effect. Both drugs have neuroprotective action and reduce oxidative stress. In animal studies, ebselen affected neurotransmitters involved in the development of mental health symptoms, and in particular, produced effects of serotonin function very similar to lithium. Both ebselen and lithium share behavioural effects: antidepressant-like effects in rodent models of depression and decrease in behavioural impulsivity, a property associated with lithium's anti-suicidal action. Human neuropsychological studies support an antidepressant profile for ebselen based on its positive impact on emotional processing and reward seeking. Our group currently is exploring ebselen’s effects in patients with mood disorders. A completed ‘add-on’ clinical trial in mania showed ebselen’s superiority over placebo after three weeks of treatment. Our ongoing experimental research explores ebselen’s antidepressant profile in patients with treatment resistant depression. If successful, this will lead to a clinical trial of ebselen as an antidepressant augmentation agent, similar to lithium.

Sex-based modulation of cognitive processes could set the stage for individual differences in vulnerability to neuropsychiatric disorders. While value-based decision making processes in particular have been proposed to be influenced by sex differences, the overall correct performance in decision making tasks often show variable or minimal differences across sexes. Computational tools allow us to uncover latent variables that define different decision making approaches, even in animals with similar correct performance. Here, we quantify sex differences in mice in the latent variables underlying behavior in a classic value-based decision making task: a restless two-armed bandit. While male and female mice had similar accuracy, they achieved this performance via different patterns of exploration. Male mice tended to make more exploratory choices overall, largely because they appeared to get ‘stuck’ in exploration once they had started. Female mice tended to explore less but learned more quickly during exploration. Together, these results suggest that sex exerts stronger influences on decision making during periods of learning and exploration than during stable choices. Exploration during decision making is altered in people diagnosed with addictions, depression, and neurodevelopmental disabilities, pinpointing the neural mechanisms of exploration as a highly translational avenue for conferring sex-modulated vulnerability to neuropsychiatric diagnoses.

The overall aim of my research is to understand how the organisation of the synapse, with particular reference to the postsynaptic proteome (PSP) of excitatory synapses in the brain, informs the fundamental mechanisms of learning, memory and behaviour and how these mechanisms go awry in neurological dysfunction. The PSP indeed bears a remarkable burden of disease, with components being disrupted in disorders (synaptopathies) including schizophrenia, depression, autism and intellectual disability. Our work has been fundamental in revealing and then characterising the unprecedented complexity (>1000 highly conserved proteins) of the PSP in terms of the subsynaptic architecture of postsynaptic proteins such as PSD95 and how these proteins assemble into complexes and supercomplexes in different neurons and regions of the brain. Characterising the PSPs in multiple species, including human and mouse, has revealed differences in key sets of functionally important proteins, correlates with brain imaging and connectome data, and a differential distribution of disease-relevant proteins and pathways. Such studies have also provided important insight into synapse evolution, establishing that vertebrate behavioural complexity is a product of the evolutionary expansion in synapse proteomes that occurred ~500 million years ago. My lab has identified many mutations causing cognitive impairments in mice before they were found to cause human disorders. Our proteomic studies revealed that >130 brain diseases are caused by mutations affecting postsynaptic proteins. We uncovered mechanisms that explain the polygenic basis and age of onset of schizophrenia, with postsynaptic proteins, including PSD95 supercomplexes, carrying much of the polygenic burden. We discovered the “Genetic Lifespan Calendar”, a genomic programme controlling when genes are regulated. We showed that this could explain how schizophrenia susceptibility genes are timed to exert their effects in young adults. The Genes to Cognition programme is the largest genetic study so far undertaken into the synaptic molecular mechanisms underlying behaviour and physiology. We made important conceptual advances that inform how the repertoire of both innate and learned behaviours is built from unique combinations of postsynaptic proteins that either amplify or attenuate the behavioural response. This constitutes a key advance in understanding how the brain decodes information inherent in patterns of nerve impulses, and provides insight into why the PSP has evolved to be so complex, and consequently why the phenotypes of synaptopathies are so diverse. Our most recent work has opened a new phase, and scale, in understanding synapses with the first synaptome maps of the brain. We have developed next-generation methods (SYNMAP) that enable single-synapse resolution molecular mapping across the whole mouse brain and extensive regions of the human brain, revealing the molecular and morphological features of a billion synapses. This has already uncovered unprecedented spatiotemporal synapse diversity organised into an architecture that correlates with the structural and functional connectomes, and shown how mutations that cause cognitive disorders reorganise these synaptome maps; for example, by detecting vulnerable synapse subtypes and synapse loss in Alzheimer’s disease. This innovative synaptome mapping technology has huge potential to help characterise how the brain changes during normal development, including in specific cell types, and with degeneration, facilitating novel pathways to diagnosis and therapy.

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.

Even if major depression is now the most common of psychiatric disorders, successful antidepressant treatments are still difficult to achieve. Therefore, a better understanding of the mechanisms of action of current antidepressant treatments is needed to ultimately identify new targets and enhance beneficial effects. Given the intimate relationships between astrocytes and neurons at synapses and the ability of astrocytes to "sense" neuronal communication and release gliotransmitters, an attractive hypothesis is emerging stating that the effects of antidepressants on brain function could be, at least in part, modulated by direct influences of astrocytes on neuronal networks. We will present two preclinical studies revealing a permissive role of glia in the antidepressant response: i) Control of the antidepressant-like effects of rat prefrontal cortex Deep Brain Stimulation (DBS) by astroglia, ii) Modulation of antidepressant efficacy of Bright Light Stimulation (BLS) by lateral habenula astroglia. Therefore, it is proposed that an unaltered neuronal-glial system constitutes a major prerequisite to optimize antidepressant efficacy of DBS or BLS. Collectively, these results pave also the way to the development of safer and more effective antidepressant strategies.

Neuronal plasticity has for a long time been considered important for the recovery from depression and for the antidepressant drug action, but how the drug action is translated to plasticity has remained unclear. Brain-derived neurotrophic factor (BDNF) and its receptor TRKB are critical regulators of neuronal plasticity and have been implicated in the antidepressant action. We have recently found that many, if not all, different antidepressants, including serotonin selective SSRIs, tricyclic as well as fast-acting ketamine, directly bind to TRKB, thereby promoting TRKB translocation to synaptic membranes, which increases BDNF signaling. We have previously shown that antidepressant treatment induces a juvenile-like state of activity in the cortex that facilitates beneficial rewiring of abnormal networks. We recently showed that activation of TRKB receptors in parvalbumin-containing interneurons orchestrates cortical activation states and is both necessary and sufficient for the antidepressantinduced cortical plasticity. Our findings open a new framework how the action of antidepressants act: rather than regulating brain monoamine concentrations, antidepressants directly bind to TRKB and allosterically promote BDNF signaling, thereby inducing a state of plasticity that allows re-wiring of abnormal networks for better functionality.

The World Health Organization (WHO) estimates that untreated mental disorders accountfor 13% of the total global burden of disease, and by 2030, depression alone will be the leadingcause of disability around the world – outpacing heart disease, cancer, and HIV. This grim pictureis further compounded by the mental health burden delivered by the coronavirus pandemic.The lack of novel treatment options in psychiatry is restricted by a limited understanding in theneuroscience basis of mental disorders, availability of relevant biomarkers, poor predictability inanimal models, and high failure rates in psychiatric drug development. However, theannouncement in 2019 from the Federal Drug Administration (FDA) for approvals of newinterventions for treatment-resistant depression (intranasal esketamine) and postpartumdepression (i.v. brexanolone), demand critical attention. Novel public-private partnerships indrug discovery, new translational data on co-morbid biology, in particular the ascendance ofpsycho-immunology, have highlighted the arrival of a new frontier in biological psychiatryresearch for depressive disorders.

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.

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.

Migraine is much more than an episodic headache. It is a complex brain disorder, characterized by a global dysfunction in multisensory information processing and integration. In a third of patients, the headache is preceded by transient sensory disturbances (aura), whose neurophysiological correlate is cortical spreading depression (CSD). The molecular, cellular and circuit mechanisms of the primary brain dysfunctions that underlie migraine onset, susceptibility to CSD and altered sensory processing remain largely unknown and are major open issues in the neurobiology of migraine. Genetic mouse models of a rare monogenic form of migraine with aura provide a unique experimental system to tackle these key unanswered questions. I will describe the functional alterations we have uncovered in the cerebral cortex of genetic mouse models and discuss the insights into the cellular and circuit mechanisms of migraine obtained from these findings.

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.

This seminar will focus on the extraordinary shift in migraine research during the last 4 decades with the discovery of the trigeminovascular system (TVS) and it’s major impact on pathophysiology and treatment.  Compelling evidence supporting the importance of TVS, cortical spreading depression and parameningeal inflammation will be explored as will the implications of newly discovered microvascular channels within the meninges on an attack.

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.

Adult hippocampal neurogenesis is implicated in memory formation and mood regulation. The Thuret lab investigates environmental and molecular mechanisms controlling the production of these adult-born neurons and how they impact mental health. We study neurogenesis in healthy ageing as well as in the context of diseases such as Alzheimer’s and depression. By approaching neurogenesis in health and disease, the strategy is two folds: (i) Validating the neurogenic process as a target for prevention and pharmacological interventions. (ii) Developing neurogenesis as a biomarker of disease prediction and progression. In this talk, I will focus on presenting some recent human studies demonstrating how hippocampal neural stem cells fate can be used as biomarkers of cognitive aging and dementia.

Lifelong devotion to headache research has led to many discoveries. First a series of studies of brain blood flow during attacks of migraine. The results showed changes compatible with cortical spreading depression in migraine without aura effectively negating the then prevailing vasospastic/ischemic theory. In migraine without aura no changes in brain blood flow. This difference was crucial for the separation of migraine with aura and migraine without aura in the first and subsequent editions of the international headache classification headed by me. Then a human migraine provocation model that has elucidated the molecular mechanisms of migraine. Successively we showed in series of papers the importance of nitric oxide, histamine, CGRP, PACAP and prostanoids. Therapeutic effectiveness of antagonizing these provokers by tonabersat, L-NMMA, CGRP receptor antagonists and monoclonal antibodies and of NSAIDs. Present and future attempts to put all these signaling mechanisms into a framework but it is not easy

Mental Health problems among youth constitutes an area of significant social, educational, clinical, policy and public health concern. Understanding processes and mechanisms that underlie the development of mental health problems during childhood and adolescence requires theoretical and methodological integration across multiple scientific domains, including developmental science, neuroscience, genetics, education and prevention science. The primary focus of this presentation is to examine the relative role of genetic and family environmental influences on children’s emotional and behavioural development. Specifically, a complementary array of genetically sensitive and longitudinal research designs will be employed to examine the role of early environmental adversity (e.g. inter-parental conflict, negative parenting practices) relative to inherited factors in accounting for individual differences in children’s symptoms of psychopathology (e.g. depression, aggression, ADHD ). Examples of recent applications of this research to the development of evidence-based intervention programmes aimed at reducing psychopathology in the context of high-risk family settings will also be presented.

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.

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.

Drosophila can learn to associate odours with reward or punishment and the resulting memories direct odour-specific approach or avoidance behaviours. Recent progress has revealed a straightforward model for learning in which reinforcing dopaminergic neurons assign valence to odour representations in the neural ensemble of the mushroom bodies. Dopamine directed synaptic depression alters the route of odour-driven activity through the mushroom body output network. This circuit configuration and influence of internal state guide the expression of appropriate behaviour. Importantly, learned behaviour is flexible and can be updated as the fly accumulates additional experience. Our latest studies demonstrate that well-informed behaviour is guided by combining parallel conflicting and complementary memories of opposite valence.

Are the immune system, brain, mind and mood related? Could this explain why chronic low-grade peripheral inflammation is also noted in approximately 1/3 of those with major depressive disorder (MDD)? The field recognized today as immunopsychiatry was founded on scientific evidence that germinated over 30 years ago. Since, it has been understood that (i) there could be a causal link between inflammation and depression, (ii) select blood immune markers show robust potential as biomarkers for inflammation-linked depression, and more generally, (iii) Descartes' theories on mind-body dualism were biologically erroneous. Nonetheless, the mechanistic brain-immune axis in the trinity formulating inflammation-linked depression i.e. psycho-neuro-immunology, still remains unclear. This talk will discuss findings from our recent investigation endeavored to unpack this by linking functional connectivity abnormalities with peripheral immune markers.

Major depressive disorder (MDD) is a sexually dimorphic disease. This sexual dimorphism is believed to result from sex-specific molecular alterations affecting functional pathways regulating the capacity of men and women to cope with daily life stress differently. Transcriptional changes associated with epigenetic alterations have been observed in the brain of men and women with depression and similar changes have been reported in different animal models of stress-induced depressive-like behaviors. In fact, most of our knowledge of the biological basis of MDD is derived from studies of chronic stress models in rodents. However, while these models capture certain aspects of the features of MDD, the extent to which they reproduce the molecular pathology of the human syndrome remains unknown and the functional consequences of these changes on the neuronal networks controlling stress responses are poorly understood. During this presentation, we will first address the extent by which transcriptional signatures associated with MDD compares in men and women. We will then transition to the capacity of different mouse models of chronic stress to recapitulate some of the transcriptional alterations associated with the expression of MDD in both sexes. Finally, we will briefly elaborate on the functional consequences of these changes at the neuronal level and conclude with an integrative perspective on the contribution of sex-specific transcriptional profiles on the expression of stress responses and MDD in men and women.

My research focuses, broadly speaking, on how emotions impact decision making. Specifically, I am interested in affective biases, a phenomenon known to be important in depression. Using a rodent decision-making task, combined with computational modelling I have investigated how different antidepressant and pro-depressant manipulations that are known to alter mood in humans alter judgement bias, and provided insight into the decision processes that underlie these behaviours. I will also highlight how the combination of behaviour and modelling can provide a truly translation approach, enabling comparison and interpretation of the same cognitive processes between animal and human research.

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.

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.

Mammalian babies are “sensory traps” for parents. Various sensory cues from the newborn are tremendously efficient in triggering parental responses in caregivers. We recently showed that core aspects of maternal behavior such as pup retrieval in response to infant vocalizations rely on active learning of auditory cues from pups facilitated by the neurohormone oxytocin (OT). Release of OT from the hypothalamus might thus help induce recognition of different infant cues but it is unknown what sensory stimuli can activate OT neurons. I performed unprecedented in vivo whole-cell and cell-attached recordings from optically-identified OT neurons in awake dams. I found that OT neurons, but not other hypothalamic cells, increased their firing rate after playback of pup distress vocalizations. Using anatomical tracing approaches and channelrhodopsin-assisted circuit mapping, I identified the projections and brain areas (including inferior colliculus, auditory cortex, and posterior intralaminar thalamus) relaying auditory information about social sounds to OT neurons. In hypothalamic brain slices, when optogenetically stimulating thalamic afferences to mimic high-frequency thalamic discharge, observed in vivo during pup calls playback, I found that thalamic activity led to long-term depression of synaptic inhibition in OT neurons. This was mediated by postsynaptic NMDARs-induced internalization of GABAARs. Therefore, persistent activation of OT neurons following pup calls in vivo is likely mediated by disinhibition. This gain modulation of OT neurons by infant cries, may be important for sustaining motivation. Using a genetically-encoded OT sensor, I demonstrated that pup calls were efficient in triggering OT release in downstream motivational areas. When thalamus projections to hypothalamus were inhibited with chemogenetics, dams exhibited longer latencies to retrieve crying pups, suggesting that the thalamus-hypothalamus noncanonical auditory pathway may be a specific circuit for the detection of social sounds, important for disinhibiting OT neurons, gating OT release in downstream brain areas, and speeding up maternal behavior.

Carnosine is a natural dipeptide widely distributed in mammalian tissues and exists at particularly high concentrations in skeletal and cardiac muscles and brain. A growing body of evidence shows that carnosine is involved in many cellular defense mechanisms against oxidative stress, including inhibition of amyloid-β (Aβ) aggregation, modulation of nitric oxide (NO) metabolism, and scavenging both reactive nitrogen and oxygen species. Different types of cells are involved in the innate immune response, with macrophage cells representing those primarily activated, especially under different diseases characterized by oxidative stress and systemic inflammation such as depression and cardiovascular disorders. Microglia, the tissue-resident macrophages of the brain, are emerging as a central player in regulating key pathways in central nervous system inflammation; with specific regard to Alzheimer’s disease (AD) these cells exert a dual role: on one hand promoting the clearance of Aβ via phagocytosis, on the other hand increasing neuroinflammation through the secretion of inflammatory mediators and free radicals. The activity of carnosine was tested in an in vitro model of macrophage activation (M1) (RAW 264.7 cells stimulated with LPS + IFN-γ) and in a well-validated model of Aβ-induced neuroinflammation (BV-2 microglia treated with Aβ oligomers). An ample set of techniques/assays including MTT assay, trypan blue exclusion test, high performance liquid chromatography, high-throughput real-time PCR, western blot, atomic force microscopy, microchip electrophoresis coupled to laser-induced fluorescence, and ELISA aimed to evaluate the antioxidant and anti-inflammatory activities of carnosine was employed. In our experimental model of macrophage activation (M1), therapeutic concentrations of carnosine exerted the following effects: 1) an increased degradation rate of NO into its non-toxic end-products nitrite and nitrate; 2) the amelioration of the macrophage energy state, by restoring nucleoside triphosphates and counterbalancing the changes in ATP/ADP, NAD+/NADH and NADP+/NADPH ratio obtained by LPS + IFN-γ induction; 3) a reduced expression of pro-oxidant enzymes (NADPH oxidase, Cyclooxygenase-2) and of the lipid peroxidation product malondialdehyde; 4) the rescue of antioxidant enzymes expression (Glutathione peroxidase 1, Superoxide dismutase 2, Catalase); 5) an increased synthesis of transforming growth factor-β1 (TGF-β1) combined with the negative modulation of interleukines 1β and 6 (IL-1β and IL-6), and 6) the induction of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1). In our experimental model of Aβ-induced neuroinflammation, carnosine: 1) prevented cell death in BV-2 cells challenged with Aβ oligomers; 2) lowered oxidative stress by decreasing the expression of inducible nitric oxide synthase and NADPH oxidase, and the concentrations of nitric oxide and superoxide anion; 3) decreased the secretion of pro-inflammatory cytokines such as IL-1β simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1; 4) prevented Aβ-induced neurodegeneration in primary mixed neuronal cultures challenged with Aβ oligomers and these neuroprotective effects was completely abolished by SB431542, a selective inhibitor of type-1 TGF-β receptor. Overall, our data suggest a novel multimodal mechanism of action of carnosine underlying its protective effects in macrophages and microglia and the therapeutic potential of this dipeptide in counteracting pro-oxidant and pro-inflammatory phenomena observed in different disorders characterized by elevated levels of oxidative stress and inflammation such as depression, cardiovascular disorders, and Alzheimer’s disease.

A long-term treatment with antidepressants reduces the risk to develop AD and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently studied for their neuroprotective properties in AD. An impairment of neurotrophic factors signaling seems to be a common pathophysiological event in depression and AD. In particular a deficit of transforming growth factor-β1 (TGF-β1) and increased oxidative stress have been found both in depression and AD. In the present work the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype in a non-transgenic mouse model of AD (i.c.v. Aβ1-42 injection) by rescue of TGF-β1 signaling. The same drugs were also tested for their ability to modulate the expression of pro-oxidant genes as well as of genes related to the antioxidant machinery.

How does a circuit of neurons process sensory information? And how are transformations of neural signals altered by changes in synaptic strength? We investigate these questions in the context of the visual system and the lateral line of fish. A distinguishing feature of our approach is the imaging of activity across populations of synapses – the fundamental elements of signal transfer within all brain circuits. A guiding hypothesis is that the plasticity of neurotransmission plays a major part in controlling the input-output relation of sensory circuits, regulating the tuning and sensitivity of neurons to allow adaptation or sensitization to particular features of the input. Sensory systems continuously adjust their input-output relation according to the recent history of the stimulus. A common alteration is a decrease in the gain of the response to a constant feature of the input, termed adaptation. For instance, in the retina, many of the ganglion cells (RGCs) providing the output produce their strongest responses just after the temporal contrast of the stimulus increases, but the response declines if this input is maintained. The advantage of adaptation is that it prevents saturation of the response to strong stimuli and allows for continued signaling of future increases in stimulus strength. But adaptation comes at a cost: a reduced sensitivity to a future decrease in stimulus strength. The retina compensates for this loss of information through an intriguing strategy: while some RGCs adapt following a strong stimulus, a second population gradually becomes sensitized. We found that the underlying circuit mechanisms involve two opposing forms of synaptic plasticity in bipolar cells: synaptic depression causes adaptation and facilitation causes sensitization. Facilitation is in turn caused by depression in inhibitory synapses providing negative feedback. These opposing forms of plasticity can cause simultaneous increases and decreases in contrast-sensitivity of different RGCs, which suggests a general framework for understanding the function of sensory circuits: plasticity of both excitatory and inhibitory synapses control dynamic changes in tuning and gain.

During periods of persistent and inescapable stress, animals can switch from active to passive coping strategies to manage effort-expenditure. Such normally adaptive behavioural state transitions can become maladaptive in disorders such as depression. We developed a new class of multi-region recurrent neural network (RNN) models to infer brain-wide interactions driving such maladaptive behaviour. The models were trained to match experimental data across two levels simultaneously: brain-wide neural dynamics from 10-40,000 neurons and the realtime behaviour of the fish. Analysis of the trained RNN models revealed a specific change in inter-area connectivity between the habenula (Hb) and raphe nucleus during the transition into passivity. We then characterized the multi-region neural dynamics underlying this transition. Using the interaction weights derived from the RNN models, we calculated the input currents from different brain regions to each Hb neuron. We then computed neural manifolds spanning these input currents across all Hb neurons to define subspaces within the Hb activity that captured communication with each other brain region independently. At the onset of stress, there was an immediate response within the Hb/raphe subspace alone. However, RNN models identified no early or fast-timescale change in the strengths of interactions between these regions. As the animal lapsed into passivity, the responses within the Hb/raphe subspace decreased, accompanied by a concomitant change in the interactions between the raphe and Hb inferred from the RNN weights. This innovative combination of network modeling and neural dynamics analysis points to dual mechanisms with distinct timescales driving the behavioural state transition: early response to stress is mediated by reshaping the neural dynamics within a preserved network architecture, while long-term state changes correspond to altered connectivity between neural ensembles in distinct brain regions.