Joshua D. Berke

Acute Effects of Cocaine on Human Brain Activity and Emotion

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.

Mesolimbic dopamine signals the value of work

Dopamine cell firing can encode errors in reward prediction, providing a learning signal to guide future behavior. Yet dopamine is also a key modulator of motivation, invigorating current behavior. Existing theories propose that fast (phasic) dopamine fluctuations support learning, whereas much slower (tonic) dopamine changes are involved in motivation. We examined dopamine release in the nucleus accumbens across multiple time scales, using complementary microdialysis and voltammetric methods during adaptive decision-making. We found that minute-by-minute dopamine levels covaried with reward rate and motivational vigor. Second-by-second dopamine release encoded an estimate of temporally discounted future reward (a value function). Changing dopamine immediately altered willingness to work and reinforced preceding action choices by encoding temporal-difference reward prediction errors. Our results indicate that dopamine conveys a single, rapidly evolving decision variable, the available reward for investment of effort, which is employed for both learning and motivational functions.

Selective Activation of Striatal Fast-Spiking Interneurons during Choice Execution

Basal ganglia circuits are essential for the organization and execution of voluntary actions. Within the striatum, fast-spiking interneurons (FSIs) are thought to tightly regulate the activity of medium-spiny projection neurons (MSNs) through feed-forward inhibition, yet few studies have investigated the functional contributions of FSIs in behaving animals. We recorded presumed MSNs and FSIs together with motor cortex and globus pallidus (GP) neurons, in rats performing a simple choice task. MSN activity was widely distributed across the task sequence, especially near reward receipt. By contrast, FSIs showed a coordinated pulse of increased activity as chosen actions were initiated, in conjunction with a sharp decrease in GP activity. Both MSNs and FSIs were direction selective, but neighboring MSNs and FSIs showed opposite selectivity. Our findings suggest that individual FSIs participate in local striatal information processing, but more global disinhibition of FSIs by GP is important for initiating chosen actions while suppressing unwanted alternatives.

Control of Basal Ganglia Output by Direct and Indirect Pathway Projection Neurons

The direct and indirect efferent pathways from striatum ultimately reconverge to influence basal ganglia output nuclei, which in turn regulate behavior via thalamocortical and brainstem motor circuits. However, the distinct contributions of these two efferent pathways in shaping basal ganglia output are not well understood. We investigated these processes using selective optogenetic control of the direct and indirect pathways, in combination with single-unit recording in the basal ganglia output nucleus substantia nigra pars reticulata (SNr) in mice. Optogenetic activation of striatal direct and indirect pathway projection neurons produced diverse cellular responses in SNr neurons, with stimulation of each pathway eliciting both excitations and inhibitions. Despite this response heterogeneity, the effectiveness of direct pathway stimulation in producing movement initiation correlated selectively with the subpopulation of inhibited SNr neurons. In contrast, effective indirect pathway-mediated motor suppression was most strongly influenced by excited SNr neurons. Our results support the theory that key basal ganglia output neurons serve as an inhibitory gate over motor output that can be opened or closed by striatal direct and indirect pathways, respectively.

Corticostriatal Interactions during Learning, Memory Processing, and Decision Making

This mini-symposium aims to integrate recent insights from anatomy, behavior, and neurophysiology, highlighting the anatomical organization, behavioral significance, and information-processing mechanisms of corticostriatal interactions. In this summary of topics, which is not meant to provide a comprehensive survey, we will first review the anatomy of corticostriatal circuits, comparing different ways by which “loops” of cortical–basal ganglia circuits communicate. Next, we will address the causal importance and systems-neurophysiological mechanisms of corticostriatal interactions for memory, emphasizing the communication between hippocampus and ventral striatum during contextual conditioning. Furthermore, ensemble recording techniques have been applied to compare information processing in the dorsal and ventral striatum to predictions from reinforcement learning theory. We will next discuss how neural activity develops in corticostriatal areas when habits are learned. Finally, we will evaluate the role of GABAergic interneurons in dynamically transforming cortical inputs into striatal output during learning and decision making.

Fast oscillations in cortical-striatal networks switch frequency following rewarding events and stimulant drugs

Oscillations may organize communication between components of large‐scale brain networks. Although gamma‐band oscillations have been repeatedly observed in cortical‐basal ganglia circuits, their functional roles are not yet clear. Here I show that, in behaving rats, distinct frequencies of ventral striatal local field potential oscillations show coherence with different cortical inputs. The ∼50 Hz gamma oscillations that normally predominate in awake ventral striatum are coherent with piriform cortex, whereas ∼80–100 Hz high‐gamma oscillations are coherent with frontal cortex. Within striatum, entrainment to gamma rhythms is selective to fast‐spiking interneurons, with distinct fast‐spiking interneuron populations entrained to different gamma frequencies. Administration of the psychomotor stimulant amphetamine or the dopamine agonist apomorphine causes a prolonged decrease in ∼50 Hz power and increase in ∼80–100 Hz power. The same frequency switch is observed for shorter epochs spontaneously in awake, undrugged animals and is consistently provoked for < 1 s following reward receipt. Individual striatal neurons can participate in these brief high‐gamma bursts with, or without, substantial changes in firing rate. Switching between discrete oscillatory states may allow different modes of information processing during decision‐making and reinforcement‐based learning, and may also be an important systems‐level process by which stimulant drugs affect cognition and behavior.

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.

Uncoordinated Firing Rate Changes of Striatal Fast-Spiking Interneurons during Behavioral Task Performance

Basal ganglia circuits make key contributions to decision making. Distributed, synchronous feedforward inhibition of striatal medium spiny neurons by fast-spiking GABAergic interneurons (FSIs) has been argued to be important for the suppression of unwanted actions, and a deficit in FSIs has been found in human patients with Tourette syndrome. However, no studies have yet examined how striatal FSIs change their activity during behavioral tasks. Here I describe 36 presumed striatal FSIs recorded in rats during well practiced performance of a radial maze win–stay task. Although most FSIs showed robust task-related activity, the temporal patterns of firing rate change were highly idiosyncratic. In contrast to other classes of striatal neurons, FSIs showed little or no coordinated population response to major task events such as instruction cues or rewards. Even when multiple FSIs were recorded simultaneously from the same local region of striatum, firing rate changes were dissimilar, and no clear evidence for synchronous firing was found using cross-correlograms (18 FSI pairs examined). These results suggest that FSIs play a more complex role in the information processing achieved by striatal microcircuits than supposed by current theoretical models.

Dopamine and Glutamate Induce Distinct Striatal Splice Forms of Ania-6, an RNA Polymerase II-Associated Cyclin

Control of neuronal gene expression by drugs or neurotransmitters is a critical step in long-term neural plasticity. Here, we show that a gene induced in the striatum by cocaine or direct dopamine stimulation, ania-6, is a member of a novel family of cyclins with homology to cyclins K/T/H/C. Further, different types of neurotransmitter stimulation cause selective induction of distinct ania-6 isoforms, through alternative splicing. The longer Ania-6 protein colocalizes with nuclear speckles and is associated with key elements of the RNA elongation/processing complex, including the hyperphosphorylated form of RNA polymerase II, the splicing factor SC-35, and the p110 PITSLRE cyclin-dependent kinase. Distinct types of neuronal stimulation may therefore differentially modulate nuclear RNA processing, through altered transcription and splicing of ania-6.

Striatal Versus Hippocampal Representations During Win-Stay Maze Performance

The striatum and hippocampus are widely held to be components of distinct memory systems that can guide competing behavioral strategies. However, some electrophysiological studies have suggested that neurons in both structures encode spatial information and may therefore make similar contributions to behavior. In rats well trained to perform a win-stay radial maze task, we recorded simultaneously from dorsal hippocampus and from multiple striatal subregions, including both lateral areas implicated in motor responses to cues and medial areas that work cooperatively with hippocampus in cognitive operations. In each brain region, movement through the maze was accompanied by the continuous sequential activation of sets of projection neurons. Hippocampal neurons overwhelmingly were active at a single spatial location (place cells). Striatal projection neurons were active at discrete points within the progression of every trial-especially during choices or following reward delivery-regardless of spatial position. Place-cell-type firing was not observed even for medial striatal cells entrained to the hippocampal theta rhythm. We also examined neural coding in earlier training sessions, when rats made use of spatial working memory to guide choices, and again found that striatal cells did not show place-cell-type firing. Prospective or retrospective encoding of trajectory was not observed in either hippocampus or striatum, at either training stage. Our results indicate that, at least in this task, dorsal hippocampus uses a spatial foundation for information processing that is not substantially modulated by spatial working memory demands. By contrast, striatal cells do not use such a spatial foundation, even in medial subregions that cooperate with hippocampus in the selection of spatial strategies. The progressive dominance of a striatum-dependent strategy does not appear to be accompanied by large changes in striatal or hippocampal single-cell representations, suggesting that the conflict between strategies may be resolved elsewhere.