PhD, University of California Davis, Neuroscience (2021)
BSc, McGill University, Pharmacology & Therapeutics (2013)
Robert Malenka, Postdoctoral Faculty Sponsor
Sex-Specific Social Effects on Depression-Related Behavioral Phenotypes in Mice
2021; 11 (12)
Social interaction and empathy play critical roles in determining the emotional well-being of humans. Stress-related depression and anxiety can be exacerbated or mitigated depending on specific social conditions. Although rodents are well known to exhibit emotional contagion and consolation behavior, the effects of group housing on stress-induced phenotypes in both males and females are not well established. Here, we investigated how the presence of stressed or unstressed conspecifics within a cage impact depression-related phenotypes. We housed male and female C57BL/6J mice in same-sex groups and subjected them to either gentle handling (GH) or the daily administration of corticosterone (CORT) for 10 days. The GH and CORT treatment groups were divided into cages of unmixed (GH or CORT) and mixed (GH and CORT) treatments. Depression-related phenotypes were measured using the forced swim test (FST) and sucrose preference test (SPT). We found that mixed housing alters FST behavior in a sex-specific manner. Male mice given chronic corticosterone (CORT) that were housed in the same cage as gently handled animals (GH) exhibited increased immobility, whereas GH females housed with CORT females demonstrated the opposite effect. This study underscores the importance of social housing conditions when evaluating stress-induced behavioral phenotypes and suggests that mixed cages of GH and CORT animals yield the greatest difference between treatment groups. The latter finding has important implications for identifying therapeutics capable of rescuing stress-induced behavioral deficits in the FST.
View details for DOI 10.3390/life11121327
View details for Web of Science ID 000737560500001
View details for PubMedID 34947858
View details for PubMedCentralID PMC8705323
- The evolution of the psychedelic revolution NEUROPSYCHOPHARMACOLOGY 2022; 47 (1): 413-414
An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress.
Psychological stress affects a wide spectrum of brain functions and poses risks for many mental disorders. However, effective therapeutics to alleviate or revert its deleterious effects are lacking. A recently synthesized psychedelic analog tabernanthalog (TBG) has demonstrated anti-addictive and antidepressant potential. Whether TBG can rescue stress-induced affective, sensory, and cognitive deficits, and how it may achieve such effects by modulating neural circuits, remain unknown. Here we show that in mice exposed to unpredictable mild stress (UMS), administration of a single dose of TBG decreases their anxiety level and rescues deficits in sensory processing as well as in cognitive flexibility. Post-stress TBG treatment promotes the regrowth of excitatory neuron dendritic spines lost during UMS, decreases the baseline neuronal activity, and enhances whisking-modulation of neuronal activity in the somatosensory cortex. Moreover, calcium imaging in head-fixed mice performing a whisker-dependent texture discrimination task shows that novel textures elicit responses from a greater proportion of neurons in the somatosensory cortex than do familiar textures. Such differential response is diminished by UMS and is restored by TBG. Together, our study reveals the effects of UMS on cortical neuronal circuit activity patterns and demonstrate that TBG combats the detrimental effects of stress by modulating basal and stimulus-dependent neural activity in cortical networks.
View details for DOI 10.1038/s41380-021-01159-1
View details for PubMedID 34035476
Citizen Science: Asking questions of psychedelic microdosing
A citizen science approach to research has shown that the improvements in mood and cognition associated with psychedelic microdosing are likely due to a placebo effect.
View details for DOI 10.7554/eLife.66920
View details for Web of Science ID 000625948100001
View details for PubMedID 33648630
View details for PubMedCentralID PMC7924944
Directed Evolution of a Selective and Sensitive Serotonin Sensor via Machine Learning
2020; 183 (7): 1986-+
Serotonin plays a central role in cognition and is the target of most pharmaceuticals for psychiatric disorders. Existing drugs have limited efficacy; creation of improved versions will require better understanding of serotonergic circuitry, which has been hampered by our inability to monitor serotonin release and transport with high spatial and temporal resolution. We developed and applied a binding-pocket redesign strategy, guided by machine learning, to create a high-performance, soluble, fluorescent serotonin sensor (iSeroSnFR), enabling optical detection of millisecond-scale serotonin transients. We demonstrate that iSeroSnFR can be used to detect serotonin release in freely behaving mice during fear conditioning, social interaction, and sleep/wake transitions. We also developed a robust assay of serotonin transporter function and modulation by drugs. We expect that both machine-learning-guided binding-pocket redesign and iSeroSnFR will have broad utility for the development of other sensors and in vitro and in vivo serotonin detection, respectively.
View details for DOI 10.1016/j.cell.2020.11.040
View details for Web of Science ID 000602900800018
View details for PubMedID 33333022
View details for PubMedCentralID PMC8025677
A non-hallucinogenic psychedelic analogue with therapeutic potential
2021; 589 (7842): 474-+
The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.
View details for DOI 10.1038/s41586-020-3008-z
View details for Web of Science ID 000597793100006
View details for PubMedID 33299186
View details for PubMedCentralID PMC7874389
Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies
JOURNAL OF MEDICINAL CHEMISTRY
2020; 63 (3): 1142-1155
Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogens possess enormous potential as neurotherapeutics due to their ability to potently promote neuronal growth. Here, we report the first-ever structure-activity relationship study with the explicit goal of identifying novel psychoplastogens. We have discovered several key features of the psychoplastogenic pharmacophore and used this information to develop N,N-dimethylaminoisotryptamine (isoDMT) psychoplastogens that are easier to synthesize, have improved physicochemical properties, and possess reduced hallucinogenic potential as compared to their DMT counterparts.
View details for DOI 10.1021/acs.jmedchem.9b01404
View details for Web of Science ID 000514221700016
View details for PubMedID 31977208
View details for PubMedCentralID PMC7075704
Psychedelic Microdosing: Prevalence and Subjective Effects
JOURNAL OF PSYCHOACTIVE DRUGS
2020; 52 (2): 113-122
Anecdotal reports suggest that the administration of sub-hallucinogenic doses of psychedelic compounds on a chronic, intermittent schedule - a practice known as psychedelic microdosing - is becoming increasingly popular among young adults due to its purported ability to reduce symptoms of depression and anxiety while improving cognitive function and promoting social interaction. Using an anonymous online survey, we collected data from 2347 people to 1) assess the prevalence of psychedelic microdosing and characterize the demographics of microdosers, 2) determine whether microdosers associate the practice with changes in mood, cognitive function, social interaction, or physiology, and 3) investigate frequent motives for discontinuing the practice. Fifty-nine percent of respondents (NT = 2183) reported familiarity with the concept of psychedelic microdosing, with 17% (383 respondents, NT = 2200) having engaged in this practice. Microdosers attributed psychedelic microdosing with improving their mood, decreasing their anxiety, and enhancing their memory, attention, and sociability. The most frequently cited reasons for quitting microdosing (NT = 243) were the risks associated with taking an illegal substance (24.28%) and the difficulty of obtaining psychedelic compounds (22.63%). Overall, our findings suggest that psychedelic microdosing is relatively common and is subjectively associated with a broad spectrum of socio-affective, cognitive, and physical outcomes.
View details for DOI 10.1080/02791072.2020.1718250
View details for Web of Science ID 000509015900001
View details for PubMedID 31973684
View details for PubMedCentralID PMC7282936
Chronic, Intermittent Microdoses of the Psychedelic N,N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents
ACS CHEMICAL NEUROSCIENCE
2019; 10 (7): 3261-3270
Drugs capable of ameliorating symptoms of depression and anxiety while also improving cognitive function and sociability are highly desirable. Anecdotal reports have suggested that serotonergic psychedelics administered in low doses on a chronic, intermittent schedule, so-called "microdosing", might produce beneficial effects on mood, anxiety, cognition, and social interaction. Here, we test this hypothesis by subjecting male and female Sprague Dawley rats to behavioral testing following the chronic, intermittent administration of low doses of the psychedelic N,N-dimethyltryptamine (DMT). The behavioral and cellular effects of this dosing regimen were distinct from those induced following a single high dose of the drug. We found that chronic, intermittent, low doses of DMT produced an antidepressant-like phenotype and enhanced fear extinction learning without impacting working memory or social interaction. Additionally, male rats treated with DMT on this schedule gained a significant amount of body weight during the course of the study. Taken together, our results suggest that psychedelic microdosing may alleviate symptoms of mood and anxiety disorders, though the potential hazards of this practice warrant further investigation.
View details for DOI 10.1021/acschemneuro.8b00692
View details for Web of Science ID 000476685400024
View details for PubMedID 30829033
View details for PubMedCentralID PMC6639775
Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT)
ACS CHEMICAL NEUROSCIENCE
2018; 9 (10): 2344-2357
Though relatively obscure, N, N-dimethyltryptamine (DMT) is an important molecule in psychopharmacology as it is the archetype for all indole-containing serotonergic psychedelics. Its structure can be found embedded within those of better-known molecules such as lysergic acid diethylamide (LSD) and psilocybin. Unlike the latter two compounds, DMT is ubiquitous, being produced by a wide variety of plant and animal species. It is one of the principal psychoactive components of ayahuasca, a tisane made from various plant sources that has been used for centuries. Furthermore, DMT is one of the few psychedelic compounds produced endogenously by mammals, and its biological function in human physiology remains a mystery. In this review, we cover the synthesis of DMT as well as its pharmacology, metabolism, adverse effects, and potential use in medicine. Finally, we discuss the history of DMT in chemical neuroscience and why this underappreciated molecule is so important to the field of psychedelic science.
View details for DOI 10.1021/acschemneuro.8b00101
View details for Web of Science ID 000447954300007
View details for PubMedID 30036036
Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression
ACS CHEMICAL NEUROSCIENCE
2018; 9 (7): 1582-1590
Depression and anxiety disorders are debilitating diseases resulting in substantial economic costs to society. Traditional antidepressants often take weeks to months to positively affect mood and are ineffective for about 30% of the population. Alternatives, such as ketamine, a dissociative anesthetic capable of producing hallucinations, and the psychoactive tisane ayahuasca, have shown great promise due to their fast-acting nature and effectiveness in treatment-resistant populations. Here, we investigate the effects of N, N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague-Dawley rats. We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants. Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.
View details for DOI 10.1021/acschemneuro.8b00134
View details for Web of Science ID 000439531400009
View details for PubMedID 29664276
View details for PubMedCentralID PMC7196340
Psychedelics Promote Structural and Functional Neural Plasticity
2018; 23 (11): 3170-3182
Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
View details for DOI 10.1016/j.celrep.2018.05.022
View details for Web of Science ID 000435196500006
View details for PubMedID 29898390
View details for PubMedCentralID PMC6082376