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Principal Investigator: Joseph M Martinez
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $82,180
Funding agency: National Institute of Mental Health
Project Summary
The process of selecting an action, evaluating, and storing the outcome to inform future responses requires the basal ganglia (BG) and extended circuits such as the lateral habenula (LHb). Indeed, perturbed LHb activity is observed in multiple human neurological disorders where action selection is impaired. This includes major depressive disorders where disrupted activity patterns in the LHb are causally related to depression-like phenotypes. Despite its critical function in action selection/outcome evaluation, the contributions of specific neuron types within the LHb to these processes in both health and disease remain incompletely understood. Previously, we defined genetically distinct neuronal subtypes within the LHb using whole transcriptome single-cell sequencing. Further, we developed a variation of a 2-armed bandit behavioral task (2ABT) that allows for manipulation and observation of LHb circuit dynamics in vivo. Utilizing these tools, we aim to study LHb activity and contribution to a behavior that requires updating action selection in uncertain contexts based on previous reward history. It is our overarching hypothesis that distinct, genetically defined LHb neuronal subtypes encode the action, the outcome, or both to differentially control action selection behavior. Stress leads to increased errors in decision making in uncertain contexts and stress or depressed patients show decreased learning rates following negative outcomes. Stressed and anxious individuals also show aversion to uncertainty, selecting more certain but less profitable outcomes rather than uncertain outcomes with higher overall profitability. Stress is a major risk factor for depressive disorder development and is known to disrupt LHb activity patterns. Increased norepinephrine (NE) signaling in the brain is a hallmark of stress response, activating in parallel with the HPA-axis contributing to both central and peripheral effects of psychosocial stress. NE stress response is known to differ between males and females. In the LHb, NE is known to contribute to states of both arousal and anxiety. Additionally, we have found differential expression of adrenergic receptors (ARs) in LHb neuronal subtypes. Consequently, we surmise LHb serves as a hub for the interaction of stress, anxiety and depressive disorders during decision making. We further hypothesize that perturbed activity in LHb neuronal subtypes underlie stress induced alterations in action selection. We will examine these hypotheses in 3 aims. In Aim 1A we will determine which genetically defined subfields encode the action, the outcome, or both during a 2ABT. In this way we will define LHb contributions to action selection. In Aim 1B we will utilize the unpredictable chronic mild stress induced anhedonia and the 2ABT to examine how chronic stress affects LHb and NE signaling during action selection. Finally in Aim 2 we will examine specific ARs in the LHb during the 2ABT. During 2ABT tasks, we predict learning of negative outcomes will be encoded by NE signaling in the LHb. Together, these aims will elucidate the mechanism by which the LHb modulates action evaluation in health and under chronic stress in male and females.
Terms: <Adrenaline><Adrenergic Receptor><Adrenoceptors><Affect><Affective Disorders><Anatomic Sites><Anatomic structures><Anatomy><Anhedonia><Animals><Anxiety><Anxiety Disorders><Arousal><Basal Ganglia><Basal Nuclei><Behavior><Behavioral><Brain><Brain Nervous System><Brain region><CNS Nervous System><CRISPR><CRISPR/Cas system><Calcium><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Chemicals><Chronic><Chronic stress><Clustered Regularly Interspaced Short Palindromic Repeats><Cues><DA Neuron><Decision Making><Degenerative Neurologic Disorders><Depressed mood><Depressive Syndromes><Depressive disorder><Development><Disease><Disorder><Disparate><Dopamine neuron><Educational process of instructing><Electrophysiology><Electrophysiology (science)><Emotional><Emotional Depression><Encephalon><Environment><Epinephrine><Epinephrine Receptors><Evaluation><Fear><Female><Fiber><Fluorescence><Fright><Future><Gene Expression><Genetic><Goals><HPA axis><Habenula><Health><History><Human><Impairment><Individual><Intracellular Communication and Signaling><Knock-out><Knockout><Lateral><Learning><Levarterenol><Levonorepinephrine><Major Depressive Disorder><Medial><Mediating><Memory><Mental Depression><Mesencephalon><Mice><Mice Mammals><Mid-brain><Midbrain><Midbrain structure><Modern Man><Mood Disorders><Murine><Mus><Nasal><Nasal Passages Nose><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neurons><Neurophysiology / Electrophysiology><Noradrenaline><Norepinephrine><Nose><Outcome><Pathogenesis><Patients><Pattern><Performance><Peripheral><Phenotype><Photometry><Play><Position><Positioning Attribute><Procedures><Process><Proxy><Psychosocial Effect><Psychosocial Stress><Punishment><Receptor Protein><Recording of previous events><Respiratory System, Nose, Nasal Passages><Rewards><Risk Factors><Role><Sensory><Signal Transduction><Signal Transduction Systems><Signaling><Single cell seq><Speed><Stimulus><Stress><Teaching><Testing><Therapeutic Epinephrine><Transgenic Mice><Transgenic Organisms><Treatment/Psychosocial Effects><Uncertainty><Update><Variant><Variation><adenoreceptor><alertness><anxious individuals><biological adaptation to stress><biological signal transduction><clinical depression><cognitive function><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><depressed><depressed patient><depression><depression symptom><depressive><depressive symptoms><developmental><differential expression><differentially expressed><dopaminergic neuron><doubt><electrophysiological><experience><global gene expression><global transcription profile><histories><hypothalamic-pituitary-adrenal (HPA) axis><hypothalamic-pituitary-adrenal axis><hypothalmus-pituitary-adrenal axis><in vivo><learning outcome><major depression><major depression disorder><male><memory retrieval><neural><neurodegenerative illness><neurological disease><neuronal><novel><patch clamp><reaction; crisis><receptor><receptor expression><response><sadness><sensor><single cell next generation sequencing><single cell sequencing><social role><stress disorder><stress response><stress; reaction><tool><transcriptional differences><transcriptome><transgenic>