Dissociable effects of dopamine on learning and performance within sensorimotor striatum

Abstract

Striatal dopamine is an important modulator of current behavior, as seen in the rapid and dramatic effects of dopamine replacement therapy in Parkinson Disease (PD). Yet there is also extensive evidence that dopamine acts as a learning signal, modulating synaptic plasticity within striatum to affect future behavior. Disentangling these “performance” and “learning” functions is important for designing effective, long-term PD treatments. We conducted a series of unilateral drug manipulations and dopamine terminal lesions in the dorsolateral striatum of rats highly-trained to perform brief instructed head/neck movements (two-alternative forced choice task). Reaction times and accuracy were measured longitudinally to determine if task behavior changed immediately, progressed over time, and/or persisted after drug withdrawal. Enhanced dopamine signaling with amphetamine caused an immediate, nonprogressive, and bilateral decrease in reaction times (RT). The altered RT distributions were consistent with reduced distance to threshold in the linear approach to threshold with ergodic rate (LATER) model of decision-making. Conversely, the dopamine antagonist flupenthixol caused experience-dependent, persistent changes in RT and accuracy indicative of a “learning” effect. These RT distributions were consistent with a slowed rate of approach to decision threshold. Our results show that dopaminergic signaling makes dissociable contributions to current and future behavior even within a single striatal subregion, and provide important clues for both models of normal decision-making and the design of novel drug therapies in PD.

Apathy and noradrenaline

“…These divergent findings call into question the impairment of implicit learning in Parkinson's disease, as well as its dependence on the dorsal striatum. It has been posited that dorsal striatal dopaminergic signals are necessary for performance, or action-selection, rather than learning per se [14,43,59,60]. These two roles may be specific to distinct striatal regions, but action-selection is often used to determine learning.…”

The missing, the short, and the long: Levodopa responses and dopamine actions

“…The decline in motor performance contralateral to the 6-hydroxydopamine lesion closely paralleled the decline in performance of unlesioned rats after unidirectional reward omission, and similar results were observed using intrastriatal injections of dopamine antagonists. 72 Striatal dopaminergic denervation mimicked extinction of a learned motor act.…”

Mouse Models of Neurodevelopmental Disease of the Basal Ganglia and Associated Circuits

“…The “short-duration response” of PD patients to levodopa, in which motor function improves on approximately the same timescale that levodopa enters the brain (Chan, Nutt, & Holford, 2004), provides strong support for this hypothesis. There is also experimental evidence that the striatum regulates online motor performance: motor output is acutely altered by intrastriatal drug infusions (Gittis et al, 2011; Leventhal et al, 2014; Worbe et al, 2009), electrical stimulation (Watanabe & Munoz, 2010), or optogenetic stimulation (Kravitz et al, 2010). …”

“…During tasks in which decisions are indicated with orienting movements to the left or right (i.e., saccades in primates or nose pokes in rodents), intrastriatal manipulations strongly bias decisions. For example, caudate microstimulation suppresses contralateral saccades (Watanabe & Munoz, 2010), and inactivation of dorsolateral striatum biases rats to move toward the inactivated side (Leventhal et al, 2014). Further, unilateral blockade of dopamine receptors or dopamine depletion biases rats toward responses ipsilateral to the lesion (Brown & Robbins, 1989; Carli, Evenden, & Robbins, 1985; Leventhal et al, 2014).…”

“…The diverse symptomatology of these diseases has strongly influenced hypotheses regarding striatal function. Broadly speaking, these hypotheses can be divided into “performance” and “learning” roles (Beeler et al, 2012; Leventhal et al, 2014). The short-duration response to levodopa is a striking example supporting a role for striatum in online motor performance.…”