The projection from the thalamic centre médian-parafascicular (CM-Pf) complex to the caudate nucleus and putamen forms a massive striatal input system in primates. We examined the activity of 118 neurons in the CM and 62 neurons in the Pf nuclei of the thalamus and 310 tonically active neurons (TANs) in the striatum in awake behaving macaque monkeys and analyzed the effects of pharmacologic inactivation of the CM-Pf on the sensory responsiveness of the striatal TANs. A large proportion of CM and Pf neurons responded to visual (53%) and/or auditory beep (61%) or click (91%) stimuli presented in behavioral tasks, and many responded to unexpected auditory, visual, or somatosensory stimuli presented outside the task context. The neurons fell into two classes: those having short-latency facilitatory responses (SLF neurons, predominantly in the Pf) and those having long-latency facilitatory responses (LLF neurons, predominantly in the CM). Responses of both types of neuron appeared regardless of whether or not the sensory stimuli were associated with reward. These response characteristics of CM-Pf neurons sharply contrasted with those of TANs in the striatum, which under the same conditions responded preferentially to stimuli associated with reward. Many CM-Pf neurons responded to alerting stimuli such as unexpected handclaps and noises only for the first few times that they occurred; after that, the identical stimuli gradually became ineffective in evoking responses. Habituation of sensory responses was particularly common for the LLF neurons. Inactivation of neuronal activity in the CM and Pf by local infusion of the GABA(A) receptor agonist, muscimol, almost completely abolished the pause and rebound facilitatory responses of TANs in the striatum. Such injections also diminished behavioral responses to stimuli associated with reward. We suggest that neurons in the CM and Pf supply striatal neurons with information about behaviorally significant sensory events that can activate conditional responses of striatal neurons in combination with dopamine-mediated nigrostriatal inputs having motivational value.

The chemogenetic technology Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) affords remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-Noxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities, and potential offtarget effects of CNO represent areas for improvement. Here we provide a new high affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg/kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg/kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents the most potent, selective, metabolically stable and fast-acting DREADD agonist reported with utility in both mice and non-human primates for a variety of applications.

Minamimoto T, La Camera G, Richmond BJ. Measuring and modeling the interaction among reward size, delay to reward and satiation level on motivation in monkeys. J Neurophysiol 101: 437-447, 2009. First published November 5, 2008 doi:10.1152/jn.90959.2008. Motivation is usually inferred from the likelihood or the intensity with which behavior is carried out. It is sensitive to external factors (e.g., the identity, amount, and timing of a rewarding outcome) and internal factors (e.g., hunger or thirst). We trained macaque monkeys to perform a nonchoice instrumental task (a sequential red-green color discrimination) while manipulating two external factors: reward size and delay-to-reward. We also inferred the state of one internal factor, level of satiation, by monitoring the accumulated reward. A visual cue indicated the forthcoming reward size and delay-to-reward in each trial. The fraction of trials completed correctly by the monkeys increased linearly with reward size and was hyperbolically discounted by delay-to-reward duration, relations that are similar to those found in free operant and choice tasks. The fraction of correct trials also decreased progressively as a function of the satiation level. Similar (albeit noiser) relations were obtained for reaction times. The combined effect of reward size, delay-to-reward, and satiation level on the proportion of correct trials is well described as a multiplication of the effects of the single factors when each factor is examined alone. These results provide a quantitative account of the interaction of external and internal factors on instrumental behavior, and allow us to extend the concept of subjective value of a rewarding outcome, usually confined to external factors, to account also for slow changes in the internal drive of the subject.

The rostromedial caudate (rmCD) of primates is thought to contribute to reward value processing, but a causal relationship has not been established. Here we use an inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drug) to repeatedly and non-invasively inactivate rmCD of macaque monkeys. We inject an adeno-associated viral vector expressing the inhibitory DREADD, hM4Di, into the rmCD bilaterally. To visualize DREADD expression in vivo, we develop a non-invasive imaging method using positron emission tomography (PET). PET imaging provides information critical for successful chemogenetic silencing during experiments, in this case the location and level of hM4Di expression, and the relationship between agonist dose and hM4Di receptor occupancy. Here we demonstrate that inactivating bilateral rmCD through activation of hM4Di produces a significant and reproducible loss of sensitivity to reward value in monkeys. Thus, the rmCD is involved in making normal judgments about the value of reward.

The centre médian-parafascicular (CM-Pf) complex is located at the posterior intralaminar nuclei of the thalamus and forms part of the nonspecific thalamocortical projection system and the internal circuit of the basal ganglia. However, the functional roles of this complex remain to be fully elucidated. Here we have examined whether the CM-Pf complex is involved in the process of covert attention. We trained two macaque monkeys to perform a task in which a visual target stimulus for button release appeared at either the same location as the preceding visual instruction cue (a "validly cued target") or a location on the opposite side (an "invalidly cued target"). Reaction times (RTs) to a validly cued target were significantly shorter than those to an invalidly cued target, leading to a "validity effect" of about 20 ms. We recorded the activity of 97 neurons in the CM-Pf while the monkeys performed the attention task with the hand that was contralateral to the neuronal recording. Seventy CM-Pf neurons showed task-related activity after the appearance of either the instruction cue or the target stimulus: 33 neurons responded with a prominent short-latency facilitation (SLF), whereas 37 responded with a short-latency suppression followed by a long-latency facilitation (LLF). Most of the SLF neurons responded preferentially to a cue appearing on the contralateral side (76%) and to an invalidly cued target appearing on the contralateral side (61%). In contrast, LLF neurons showed a short-latency suppression after the cue stimulus, regardless of whether the cue appeared on the contra- or ipsilateral side (84%). Inactivating the CM-Pf complex by local injection (1 microl) of the GABA(A) receptor agonist muscimol (1-5 microg/microl) resulted in a significant increase in the RT to a validly cued target presented on the contra- but not the ipsilateral side. In contrast, inactivating the CM-Pf complex did not affect RTs to invalidly cued targets on either the contra- or the ipsilateral side. Thus the validity effect was abolished only on the contralateral side. We conclude that the CM-Pf complex plays a specific and essential role in the process of attentional orienting to external events occurring on the contralateral side, probably through the projection of primary outputs to the striatum, which is involved in the action-selection mechanisms of the basal ganglia.

To study how the interaction between orbitofrontal (OFC) and rhinal (Rh) cortices influences the judgment of reward size, we reversibly disconnected these regions using the hM4Di-DREADD (Designer Receptor Exclusively Activated by Designer Drug). Repeated inactivation reduced sensitivity to differences in reward size in two monkeys. Results suggest that retrieval of relative stimulus values from memory appears to depend on interaction between Rh and OFC.

Activity in several areas of the human brain and the monkey brain increases when a subject anticipates events associated with a reward, implicating a role for bias of decision and action. However, in real life, events do not always appear as expected, and we must choose an undesirable action. More than half of the neurons in the monkey centromedian (CM) thalamus were selectively activated when a small-reward action was required but a large-reward option was anticipated. Electrical stimulation of the CM after a large-reward action request substituted a brisk performance with a sluggish performance. These results suggest involvement of the CM in a mechanism complementary to decision and action bias.

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