Thursday, December 26, 2024
12/26/2024
Project Summary The mesocorticostriatal network is central to adaptive reward processes, as well as diseases of dysfunctional learning, motivation, and cognition. As learning progresses, there is a transition from initial reliance on nucleus accumbens (NAC) to later recruitment of dorsolateral striatum (DLS), which drives a shift from goal-directed behavior to more automatic behaviors characterized by rapid, stimulus-driven movement sequences. This transition is thought to involve a network of recurrent loops, including dense dopaminergic (DA) input from the ventral tegmental area (VTA)/substantia nigra (SNC) and glutamatergic input from cortex. Critically, however, the contributions of these loops have not been directly tested, and the circuit mechanisms driving this fundamental neurobiological adaptation remain undefined. In the proposed studies, we will use several innovative approaches to investigate how different loop systems within the mesocorticostriatal network communicate in vivo to organize conditioned behavior, and transition from ventral to dorsal striatal control, across learning. One influential anatomical framework, the mesostriatal “spiral” hypothesis, suggests that during learning, information flows serially across a subcortical loop, from the VTA to nucleus accumbens to SNC, to dorsolateral striatum. Despite broad acceptance in the field, support for the striatal spiral has not been demonstrated in vivo. Instead, emerging evidence suggests an alternative hypothesis: that cue-reward learning engages progressive recruitment of the dorsal striatum via nigro-thalamo-cortical circuits, rather than the classic striatal spiral mechanism. In Aim 1 we will combine fiber photometry recordings of somatic DA neuron activity in TH-cre rats with simultaneous recordings of a DA biosensor in the striatum, to characterize the spatial and temporal pattern of information flow through four nodes in the striatal DA system during cue-reward (i.e., Pavlovian) learning, testing predictions from the spiral framework. In Aim 2, we will use trans-synaptic targeting, optogenetics, and photometry to test the ascending spiral framework in vivo, determining if NAC direct pathway neurons disinhibit SNC DA neurons. We will use D1-cre rats to investigate the function of direct pathway output neurons in the NAC and DLS at different stages of learning. Finally, In Aim 3 we will combine photometry recordings of corticostriatal and thalamostriatal circuits with optogenetic manipulation of DA neurons in TH-cre rats, to assess the ability of nucleus accumbens DA signaling to engage the nigro-thalamo- cortical loop. We will then optogenetically manipulate input-defined nigral neurons projecting to the thalamus to determine the functional role of the nigro-thalamo-cortical loop in learning. These studies will resolve longstanding questions about the circuit mechanisms of information flow across striatal input-output circuits, establishing a normative framework for the in vivo functional architecture of the mesocorticostriatal network.
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