Circuit-specific plasticity mechanisms for habitual behavior

The National Institute of Mental Health awarded Duke University $315,364 on November 1, 2025, under the Mental Health Research Grants program (CFDA 93.242) to support research on circuit-specific plasticity mechanisms for habitual behavior.

The project, titled "Circuit-Specific Plasticity Mechanisms for Habitual Behavior," investigates how cortical inputs to the striatum undergo long-lasting modifications during the transition from goal-directed to habitual action strategies. The research employs optogenetic approaches and two-photon imaging to measure synaptic strength of pyramidal tract and intratelencephalic tract inputs to the striatum in acute brain slices from behaviorally characterized mice, targeting orbitofrontal cortex inputs to the dorsomedial striatum and secondary motor cortex inputs to the dorsolateral striatum. The project also uses FOS-TRAP2 technology to identify novel cortical regions whose activity is modulated during behavioral transitions between goal and habit states.

The period of performance runs from November 1, 2025, through March 31, 2028, with work performed in Durham, North Carolina. This is a project grant, a form of assistance funding supporting specified research activities through Duke University's Office of Research Administration.

Abstract

The ability to learn which action strategies produce positive outcomes is a central process for adaptive behaviors. Through repetition, action strategies naturally evolve from a flexible (goal-directed) phase into an automatic (habitual) phase. The dorsal striatum is required for the transition between goal-directed and habitual action strategies. Studies over the past two decades have demonstrated that dorsomedial striatum (DMS) is required for goal behavior whereas the dorsolateral striatum (DLS) is required for habitual behavior. Numerous studies have associated long-lasting modifications of DLS circuitry with habitual behavior, but all these plasticity observations were from bulk stimulation of unidentified cortical inputs to striatum. Therefore, IT is unknown which cortical inputs to striatum undergo long-lasting modifications over the course of habit formation nor the role these plasticity sites play in habit expression. This project employs two unique strategies to fill this GAP. First, we will genetically isolate the two major types of cortical inputs to striatum, the pyramidal tract (PT) and intratelencephalic tract (IT). PT circuits are selectively active during movement; therefore, IT is possible long-term modifications of PT circuits sustain motor output for habit expression. Second, we will identify novel cortical regions whose activity is modulated by behavioral transitioning from goal to habit states using FOS-TRAP2 technology. Aim 1 will test the hypothesis that habit expression is accompanied by selective plasticity of PT inputs, and not IT, using optogenetic approaches to activate and quantitatively measure the synaptic strength (whole cell patch clamp and 2-photon imaging of gcamps) of PT and IT inputs to striatum in acute brain slices from behaviorally defined mice. I will target orbitofrontal cortex (OFC) inputs to DMS and secondary motor cortex (M2) input to DLS based on preliminary data and published studies suggesting habit is associated with weakening of OFC circuits and strengthening of M2 circuits. Outcomes will provide the first measure of these specific synapses in goal and habit states. Aim 2 will test the hypothesis that weakening OFC pyramidal tract inputs to DMS speeds habit, whereas weakening M2 pyramidal tract inputs to DLS delays habit. I will test this using cell specific pharmacology (dart technology) to dampen glutamatergic input to PT or IT cortical circuits that innervate striatum, thus establishing causal contributions of defined corticostriatal circuits to the expression of habitual behavior. Aim 3 will construct a state-dependent map of neuronal activity across cortical regions that innervate DMS and DLS using molecular genetic capture of activity ensembles (FOS-TRAP2 technology) and immuno-staining. Outcomes are expected to identify novel cortical regions associated with habitual behavior. Collectively, completion of this proposal will identify circuit-specific plasticity mechanisms involved in habitual behavior, producing a detailed plasticity model to better understand neural basis of adaptive habit formation and how disruptions in this process may accompany numerous neuropsychiatric disorders.