Abstract Chronic stress has lasting adverse consequences that can lead, over time, to depressive disorders1‑4 yet identifying the optimal timeframe for effective therapies remains an unmet challenge. Enhanced neuronal activity and disrupted aversion-encoding in lateral habenula (LHb) are important mediators of stress-related behavioral repercussions5‑10, although the precise timing of its...
Lysergic acid diethylamide (LSD) is a potent psychedelic with increasing therapeutic interest, yet qualification of target engagement using in vivo neuroimaging has not yet been performed. Using simultaneous positron emission tomography-magnetic resonance imaging technology, we describe multiple brain actions of LSD in seven healthy volunteers blinded to LSD dose received. Here we show that LSD...
Psychedelics, known for prosocial effects and therapeutic potential in psychiatry, are often first used during adolescence, yet their enduring impact on social behavior and its underlying circuits remain unclear. Here we show that repeated exposure to the serotonergic psychedelic drug 25C-NBOMe during adolescence, but not exposure in adulthood, induced lasting competitive avoidance in male...
Psychedelic science is growing rapidly and offers great promise for exciting new therapies, but this rapid growth has brought growing pains. These include a lack of appreciation of the history of the field and what has already been accomplished, and a lack of understanding of the pharmacology of psychedelics and 5-HT_2A receptors. These gaps must be recognized, acknowledged and addressed in...
Human neuroimaging studies report that psychedelics induce serotonin-2A receptor-dependent changes in functional brain reorganization, presumably reflecting neuromodulation. However, these studies often overlook the potent vasoactive effects of serotonin. Here we identified psilocybin-induced alterations in hemodynamic response functions during human functional magnetic resonance imaging,...
Chronic pain and mood disorders co-occur, exacerbate one another and share neurobiological mechanisms, but whether a single intervention could promptly alleviate both conditions remains unclear. Here, in two chronic pain models, we show that a single dose of psilocybin induces a rapid and sustained reversal of both mechanical allodynia and anxiodepression-like states in adult male and female...
Nonhallucinogenic psychoplastogens, such as tabernanthalog (TBG), are being developed as potentially safer, more scalable alternatives to psychedelics for promoting neuronal growth and treating various brain conditions. Currently, it is unclear whether 5-hydroxytryptamine 2A (5-HT2A) receptors and immediate early gene (IEG) activation have a role in the neuroplasticity-promoting effects of...
The choroid plexus (ChP) regulates cerebrospinal fluid (CSF) composition, providing essential molecular cues for brain development; yet, embryonic ChP secretory mechanisms remain poorly defined. Here we identify apocrine secretion by embryonic ChP epithelial cells as a key regulator of the CSF proteome and neurodevelopment in male and female mice. We demonstrate that the activation of...
The psychedelic drug psilocybin demonstrates rapid and long-lasting efficacy across neuropsychiatric disorders that are characterized by behavioral inflexibility. However, its impact on the neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test whether psilocybin enhances behavioral flexibility by altering activity in cortical neural...
The default mode network (DMN) is implicated in many aspects of complex thought and behavior. Here, we leverage postmortem histology and in vivo neuroimaging to characterize the anatomy of the DMN to better understand its role in information processing and cortical communication. Our results show that the DMN is cytoarchitecturally heterogenous, containing cytoarchitectural types that are...
Abstract Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to...
Psychedelics are serotonin 2A receptor agonists that can lead to profound changes in perception, cognition and mood. In this review, we focus on the basic neurobiology underlying the action of psychedelic drugs. We first discuss chemistry, highlighting the diversity of psychoactive molecules and the principles that govern their potency and pharmacokinetics. We describe the roles of serotonin...
We show that the sex of human experimenters affects mouse behaviors and responses following administration of the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. Mice showed aversion to the scent of male experimenters, preference for the scent of female experimenters and increased stress susceptibility when handled by male experimenters. This...
Nature NeuroscienceSeptember 11, 2019R. Frau, Vivien Miczán, F. Traccis et al.
The increased legal availability of cannabis has led to a common misconception that it is a safe natural remedy for, among others, pregnancy-related ailments such as morning sickness. Emerging clinical evidence, however, indicates that prenatal cannabis exposure (PCE) predisposes offspring to various neuropsychiatric disorders linked to aberrant dopaminergic function. Yet, our knowledge of how...
Consciousness never fades during waking. However, when awakened from sleep, we sometimes recall dreams and sometimes recall no experiences. Traditionally, dreaming has been identified with rapid eye-movement (REM) sleep, characterized by wake-like, globally 'activated', high-frequency electroencephalographic activity. However, dreaming also occurs in non-REM (NREM) sleep, characterized by...
Recent findings link fronto-temporal gamma electroencephalographic (EEG) activity to conscious awareness in dreams, but a causal relationship has not yet been established. We found that current stimulation in the lower gamma band during REM sleep influences ongoing brain activity and induces self-reflective awareness in dreams. Other stimulation frequencies were not effective, suggesting that...
In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates...
Nature NeuroscienceJanuary 8, 2012Cristiano Nazzaro, Barbara Greco, Milica Cerovic et al.
Endocannabinoids (eCBs) regulate neuronal activity in the dorso-lateral striatum (DLS), a brain region that is involved in habitual behaviors. How synaptic eCB signaling contributes to habitual behaviors under physiological and pathological conditions remains unclear. Using a mouse model of cannabinoid tolerance, we found that persistent activation of the eCB pathway impaired eCB-mediated...
The surface area of human primary visual cortex (V1) varies substantially between individuals for unknown reasons. We found that this variability was strongly and negatively correlated with the magnitude of two common visual illusions, where two physically identical objects appear different in size as a result of their context. Because such illusions dissociate conscious perception from...
The lack of an accepted measure of awareness has made claims that accurate decisions can be made without awareness controversial. Here we introduce a new objective measure of awareness, post-decision wagering. We show that participants fail to maximize cash earnings by wagering high following correct decisions in blindsight, the Iowa gambling task and an artificial grammar task. This...
Nature NeuroscienceJune 2004Susana Mato, Vivien Chevaleyre, David Robbe et al.
Endogenous cannabinoids (eCB) mediate synaptic plasticity in brain regions involved in learning and reward. Here we show that in mice, a single in-vivo exposure to Delta 9-tetrahydrocannabinol (THC) abolishes the retrograde signaling that underlies eCB-mediated synaptic plasticity in both nucleus accumbens (NAc) and hippocampus in vitro. This effect is reversible within 3 days and is associated...
Nature NeuroscienceJanuary 2004Angela Sirigu, Elena Daprati, Sophie Ciancia et al.
A central question in the study of human behavior is the origin of willed action. EEG recordings of surface brain activity from human subjects performing a self-initiated movement show that the subjective experience of wanting to move follows, rather than precedes, the 'readiness potential'--an electrophysiological mark of motor preparation. This raises the issue of how conscious experience of...
Here we summarize our present approach to the problem of consciousness. After an introduction outlining our general strategy, we describe what is meant by the term 'framework' and set it out under ten headings. This framework offers a coherent scheme for explaining the neural correlates of (visual) consciousness in terms of competing cellular assemblies. Most of the ideas we favor have been...