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Principal Investigator: Michael L Wallace
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $561,579
Funding agency: National Institute of Mental Health
Project Summary
Serotonin (5-HT)-releasing neurons in the mammalian mid/hindbrain are critical for fundamental behaviors and
cognitive processes, including emotional control, arousal, and motor control. Selective serotonin reuptake
inhibitors (SSRIs) increase brain 5-HT levels and are the most commonly prescribed treatment for major-
depression in humans. However, our understanding of the mechanisms by which 5-HT influences synapses,
cells, and circuits is limited, prohibiting improvement of depression therapeutics. A major target of 5-HT
neurons is the lateral habenula (LHb), a subcortical structure principally implicated in evaluating the outcome
(positive or negative) of an action. The LHb is the only brain region that shows consistent hyperactivity several
rodent models of chronic stress and additional studies have recently refined this observation indicating “burst-
firing” in LHb is causally related several behavioral phenotypes (including anhedonia) following chronic stress.
Recently, using single-cell transcriptome wide sequencing, we genetically defined the neuronal subclasses
within the LHb for the first time revealing cell-type specific expression of both 5-HT receptors and genes
related to burst-firing. Our central hypothesis is that 5-HT release dynamically modulates the habenula circuit
though neuron-type specific expression of 5-HT receptors and that burst-firing in specific, genetically defined
LHb neuron-types is required for anhedonia following chronic stress. This proposal seeks to 1) identify the
neuron-type(s) in the LHb that exhibit burst-firing in vitro and in vivo, 2) determine how 5-HT modulates
neuron-types and local connectivity within the LHb and 3) define the neuron-types in the LHb required for
chronic stress induced anhedonia. By revealing how 5-HT modulates habenular circuits, the proposed work
will provide a comprehensive understanding of the cellular and circuit targets of this important neuromodulator.
These findings will form the foundation for understanding the principal mechanisms by which SSRIs impact
synapses and circuits of the LHb, uncovering new avenues for therapeutic intervention in major depressive
disorder and other neurological disorders treated by these drugs.
Terms: <5-HT><5-HT Receptors><5-Hydroxytryptamine><5-Hydroxytryptamine Receptors><5HT><Action Potentials><Acute><Affect><Anhedonia><Arousal><Axon><Behavior><Behavioral><Brain><Brain Nervous System><Brain region><Calcium><Cell Body><Cells><Chronic stress><Color><Data><Disease><Disorder><Dopamine><Drugs><Electrophysiology><Electrophysiology (science)><Emotional><Encephalon><Enteramine><Exhibits><Fire - disasters><Fires><Fore-Brain><Forebrain><Foundations><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Genes><Habenula><Head><Hind Brain><Hippophaine><Human><Hydroxytyramine><Hyperactivity><In Vitro><In vivo analysis><Individual><Ion Channel><Ionic Channels><Lateral><Learning><Levarterenol><Levonorepinephrine><Link><Longitudinal Studies><Major Depressive Disorder><Measures><Mediator><Medication><Membrane Channels><Mental Depression><Mental disorders><Mental health disorders><Mesencephalon><Methods><Mice><Mice Mammals><Mid-brain><Midbrain><Midbrain structure><Modern Man><Murine><Mus><Nerve Cells><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Transmission><Neurocyte><Neurologic Disorders><Neurological Disorders><Neuromodulator><Neurons><Neurophysiology / Electrophysiology><Noradrenaline><Norepinephrine><Optics><Outcome><Pattern><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Prosencephalon><Psychiatric Disease><Psychiatric Disorder><Psychiatric therapeutic procedure><Psychological reinforcement><Receptor Protein><Reinforcement><Reporting><Rhombencephalon><Rodent Model><SSRI><SSRIs><Selective Serotonin Reuptake Inhibitor><Selective serotonin re-uptake inhibitor><Serotonin><Stress><Structure><Synapses><Synaptic><Synaptic Transmission><Techniques><Testing><Therapeutic><Therapeutic Intervention><Time><Work><anti-depressant agent><anti-depressant drugs><anti-depressants><anti-depressive agents><behavior phenotype><behavioral phenotyping><cell type><clinical depression><cognitive process><common treatment><depression><differential expression><differentially expressed><drug/agent><electrophysiological><fire><fluorophore><global gene expression><global transcription profile><hindbrain><improved><in vivo><in vivo evaluation><in vivo testing><intervention therapy><long-term study><longitudinal outcome studies><longterm study><major depression><major depression disorder><memory process><memory processing><mental illness><motivated behavior><motor control><neural circuit><neural circuitry><neurocircuitry><neurological disease><neuronal><neuronal circuit><neuronal circuitry><optical><pharmaceutical><psychiatric care><psychiatric illness><psychiatric therapy><psychiatric treatment><psychological disorder><receptor><sensor><serotonin receptor><serotonin reuptake inhibitor><spatiotemporal><synapse><synaptic circuit><synaptic circuitry><transcriptional differences><transcriptome><transcriptomics>