Cortico-striatal activity driving compulsive reward seeking

Abstract

Loss of control over drug intake and persistent drug-seeking despite negative consequences define addiction. Increase dopamine levels in the mesolimbic system may constitute the initial trigger. Optogenetic self-stimulation of VTA DA neurons (oDASS) has thus been proposed as an addiction model. Indeed, lever pressing to turn on a laser aimed at ChR2 expressing DA neurons is strongly reinforcing. Clinical observations indicate that drug-seeking even with the risk of harmful consequences occurs only in a fraction of users, with chronic drug consumption. Here, mice carried out a seek-take chain in order to selectively study compulsive seeking behavior. Once fully established, a probabilistic punishment of the seeking lever led to the emergence of two classes of mice; those that persevered and those that renounced oDASS. Ex vivo characterization of three distinct cortico-striatal streams demonstrated a selective potentiation of excitatory synapses of the orbito-frontal cortex (OFC) to dorsal striatum projection in persevering mice. Taken together, our data indicate a gain-of-function of OFC striatal control in compulsive oDASS. Harada et al. Compulsive oDASS seeking

Striosomes Mediate Value-Based Learning Vulnerable in Age and a Huntington’s Disease Model

“…During learning, Ca 2+ transients in striosomal populations that we recorded decreased in frequency and showed a trend toward increasing amplitude. This pattern is consistent with the possibility that, as learning occurs, striosome-based circuitry undergoes refinement via plasticity mechanisms (Harada et al, 2019;Owen et al, 2018;Xiong et al, 2015;Znamenskiy and Zador, 2013). Given the slow time course of GCaMP6m signaling, the frequency and amplitude of Ca 2+ transients might reflect development of more synchronized or patterned spike activity, as indicated by an increased SNR.…”

Dopamine Signaling in the Dorsomedial Striatum Promotes Compulsive Behavior

“…1B). The shock intensity was chosen based on previous studies of punishment-resistant reward-seeking (Harada et al, 2019). We verified that this shock intensity is aversive to the mice in a fear conditioning paradigm in which 12 tone-shock pairings were delivered.…”

Dopamine signaling in the dorsomedial striatum promotes compulsive behavior

“…Enhanced activity and plasticity in orbitofrontal cortex to DMS projections have been observed in animals that compulsively self-stimulate their ventral tegmental area (VTA) dopamine neurons and in animals that compulsively self-administer methamphetamine. [12][13][14][15] To distinguish between these hypotheses, we trained mice to work for sucrose on a random interval schedule (RI60) known to promote habit and tested whether they became punishment resistant. We used fiber photometry to record dopamine axon activity in DMS and DLS during this behavior.…”