Valuation and Decision-Making in Cortical-Striatal Circuits.

Adaptive decision-making relies on a distributed network of neural substrates that learn associations between behaviors and outcomes, to ultimately guide future behavior. These substrates are organized in a system of cortical-striatal loops that offer unique contributions to goal-directed behavior and receive prominent inputs from the midbrain dopamine system. However, the consequences of dopamine fluctuations at these targets remain largely unresolved, despite aggressive interrogation. Some experiments have highlighted dopamine’s role in learning via reward prediction errors, while others have noted the importance of dopamine in motivated behavior. Here, we explored the precise role of dopamine in shaping decision-making in cortex and striatum. First, we measure dopamine in ventral striatum during a trial-and-error task and show that it uniformly encodes a moment-by-moment estimate of value across multiple timescales. Our optogenetic manipulations demonstrate that changes in this value signal can be used to immediately enhance vigor, consistent with a motivational signal, and alter subsequent choice behavior, consistent with a learning signal. Next, I measured dopamine in multiple cortical-striatal loops to examine the uniformity of the value signal. I report that dopamine is non-uniform across circuits, but is consistent within them, implying that dopamine may offer unique contributions to the information processed in each loop. Finally, I performed single-unit recordings in the dorsal striatum, a major recipient of dopamine, to examine whether distinct its subcompartments—the patch and matrix—carry distinct value signals used in the selection of actions. I report preliminary data and summarize improvements in my electrode localization technique.PhDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/133227/1/jpettibo_1.pd

Selective Inhibition of Striatal Fast-Spiking Interneurons Causes Dyskinesias

http://deepblue.lib.umich.edu/bitstream/2027.42/177392/2/15727.full.pdfPublished versionDescription of 15727.full.pdf : Published versio

Selective inhibition of striatal fast-spiking interneurons causes dyskinesias.

Fast-spiking interneurons (FSIs) can exert powerful control over striatal output, and deficits in this cell population have been observed in human patients with Tourette syndrome and rodent models of dystonia. However, a direct experimental test of striatal FSI involvement in motor control has never been performed. We applied a novel pharmacological approach to examine the behavioral consequences of selective FSI suppression in mouse striatum. IEM-1460, an inhibitor of GluA2-lacking AMPARs, selectively blocked synaptic excitation of FSIs but not striatal projection neurons. Infusion of IEM-1460 into the sensorimotor striatum reduced the firing rate of FSIs but not other cell populations, and elicited robust dystonia-like impairments. These results provide direct evidence that hypofunction of striatal FSIs can produce movement abnormalities, and suggest that they may represent a novel therapeutic target for the treatment of hyperkinetic movement disorders.</p

Knock-in rat lines with Cre recombinase at the dopamine D1 and adenosine 2a receptor loci

Genetically modified mice have become standard tools in neuroscience research. Our understanding of the basal ganglia in particular has been greatly assisted by BAC mutants with selective transgene expression in striatal neurons forming the direct or indirect pathways. However, for more sophisticated behavioral tasks and larger intracranial implants, rat models are preferred. Furthermore, BAC lines can show variable expression patterns depending upon genomic insertion site. We therefore used CRISPR/Cas9 to generate two novel knock-in rat lines specifically encoding Cre recombinase immediately after the dopamine D1 receptor (Drd1a) or adenosine 2a receptor (Adora2a) loci. Here, we validate these lines using in situ hybridization and viral vector mediated transfection to demonstrate selective, functional Cre expression in the striatal direct and indirect pathways, respectively. We used whole-genome sequencing to confirm the lack of off-target effects and established that both rat lines have normal locomotor activity and learning in simple instrumental and Pavlovian tasks. We expect these new D1-Cre and A2a-Cre rat lines will be widely used to study both normal brain functions and neurological and psychiatric pathophysiology

Dissociable dopamine dynamics for learning and motivation.

The dopamine projection from ventral tegmental area (VTA) to nucleus accumbens (NAc) is critical for motivation to work for rewards and reward-driven learning. How dopamine supports both functions is unclear. Dopamine&nbsp;cell spiking can encode prediction errors, which are&nbsp;vital learning signals in computational theories of adaptive behaviour. By contrast, dopamine release ramps up as animals approach rewards, mirroring reward expectation. This mismatch might reflect differences in behavioural tasks, slower changes in dopamine cell spiking or spike-independent modulation of dopamine release. Here we compare spiking of identified VTA dopamine cells with NAc dopamine release in the same decision-making task. Cues that&nbsp;indicate&nbsp;an upcoming reward increased both spiking and release. However, NAc core dopamine release also covaried with dynamically evolving reward expectations, without corresponding changes in VTA dopamine cell spiking. Our results suggest a fundamental difference in how dopamine release is regulated to achieve distinct functions: broadcast burst signals promote learning, whereas local control drives motivation