Environmental context-dependent activation of dopamine neurons via putative amygdala-nigra pathway in macaques.

Seeking out good and avoiding bad objects is critical for survival. In practice, objects are rarely good every time or everywhere, but only at the right time or place. Whereas the basal ganglia (BG) are known to mediate goal-directed behavior, for example, saccades to rewarding objects, it remains unclear how such simple behaviors are rendered contingent on higher-order factors, including environmental context. Here we show that amygdala neurons are sensitive to environments and may regulate putative dopamine (DA) neurons via an inhibitory projection to the substantia nigra (SN). In male macaques, we combined optogenetics with multi-channel recording to demonstrate that rewarding environments induce tonic firing changes in DA neurons as well as phasic responses to rewarding events. These responses may be mediated by disinhibition via a GABAergic projection onto DA neurons, which in turn is suppressed by an inhibitory projection from the amygdala. Thus, the amygdala may provide an additional source of learning to BG circuits, namely contingencies imposed by the environment.

Environment-based object values learned by local network in the striatum tail.

Basal ganglia contribute to object-value learning, which is critical for survival. The underlying neuronal mechanism is the association of each object with its rewarding outcome. However, object values may change in different environments and we then need to choose different objects accordingly. The mechanism of this environment-based value learning is unknown. To address this question, we created an environment-based value task in which the value of each object was reversed depending on the two scene-environments (X and Y). After experiencing this task repeatedly, the monkeys became able to switch the choice of object when the scene-environment changed unexpectedly. When we blocked the inhibitory input from fast-spiking interneurons (FSIs) to medium spiny projection neurons (MSNs) in the striatum tail by locally injecting IEM-1460, the monkeys became unable to learn scene-selective object values. We then studied the mechanism of the FSI-MSN connection. Before and during this learning, FSIs responded to the scenes selectively, but were insensitive to object values. In contrast, MSNs became able to discriminate the objects (i.e., stronger response to good objects), but this occurred clearly in one of the two scenes (X or Y). This was caused by the scene-selective inhibition by FSI. As a whole, MSNs were divided into two groups that were sensitive to object values in scene X or in scene Y. These data indicate that the local network of striatum tail controls the learning of object values that are selective to the scene-environment. This mechanism may support our flexible switching behavior in various environments.

Primate Amygdalo-Nigral Pathway for Boosting Oculomotor Action in Motivating Situations.

A primary function of the primate amygdala is to modulate behavior based on emotional cues. To study the underlying neural mechanism, we first inactivated the amygdala locally and temporarily by injecting a GABA agonist. Then, saccadic eye movements and gaze were suppressed only on the contralateral side. Next, we performed optogenetic activation after injecting a viral vector into the amygdala. Optical stimulation in the amygdala excited amygdala neurons, whereas optical stimulation of axon terminals in the substantia nigra pars reticulata inhibited nigra neurons. Optical stimulation in either structure facilitated saccades to the contralateral side. These data suggest that the amygdala controls saccades and gaze through the basal ganglia output to the superior colliculus. Importantly, this amygdala-derived circuit mediates emotional context information, whereas the internal basal ganglia circuit mediates object value information. This finding demonstrates a basic mechanism whereby basal ganglia output can be modulated by other areas conveying distinct information.

Multiple neuronal circuits for variable object-action choices based on short- and long-term memories.

At each time in our life, we choose one or few behaviors, while suppressing many other behaviors. This is the basic mechanism in the basal ganglia, which is done by tonic inhibition and selective disinhibition. Dysfunctions of the basal ganglia then cause 2 types of disorders (difficulty in initiating necessary actions and difficulty in suppressing unnecessary actions) that occur in Parkinson's disease. The basal ganglia generate such opposite outcomes through parallel circuits: The direct pathway for initiation and indirect pathway for suppression. Importantly, the direct pathway processes good information and the indirect pathway processes bad information, which enables the choice of good behavior and the rejection of bad behavior. This is mainly enabled by dopaminergic inputs to these circuits. However, the value judgment is complex because the world is complex. Sometimes, the value must be based on recent events, thus is based on short-term memories. Or, the value must be based on historical events, thus is based on long-term memories. Such memory-based value judgment is generated by another parallel circuit originating from the caudate head and caudate tail. These circuit-information mechanisms allow other brain areas (e.g., prefrontal cortex) to contribute to decisions by sending information to these basal ganglia circuits. Moreover, the basal ganglia mechanisms (i.e., what to choose) are associated with cerebellum mechanisms (i.e., when to choose). Overall, multiple levels of parallel circuits in and around the basal ganglia are essential for coordinated behaviors. Understanding these circuits is useful for creating clinical treatments of disorders resulting from the failure of these circuits.

The Caudal Part of Putamen Represents the Historical Object Value Information.

The basal ganglia, especially the circuits originating from the putamen, are essential for controlling normal body movements. Notably, the putamen receives inputs not only from motor cortical areas but also from multiple sensory cortices. However, how these sensory signals are processed in the putamen remains unclear. We recorded the activity of tentative medium spiny neurons in the caudal part of the putamen when the monkey viewed many fractal objects. We found many neurons that responded to these objects, mostly in the ventral region. We called this region "putamen tail" (PUTt), as it is dorsally adjacent to "caudate tail" (CDt). Although PUTt and CDt are mostly separated by a thin layer of white matter, their neurons shared several features. Almost all of them had receptive fields in the contralateral hemifield. Moreover, their responses were object selective (i.e., variable across objects). The object selectivity was higher in the ventral region (i.e., CDt > PUTt). Some neurons above PUTt, which we called the caudal-dorsal putamen (cdPUT), also responded to objects, but less selectively than PUTt. Next, we examined whether these visual neurons changed their responses based on the reward outcome. We found that many neurons encoded the values of many objects based on long-term memory, but not based on short-term memory. Such stable value responses were stronger in PUTt and CDt than in cdPUT. These results suggest that PUTt, together with CDt, controls saccade/attention among objects with different historical values, and may control other motor actions as well.SIGNIFICANCE STATEMENT Although the putamen receives inputs not only from motor cortical areas but also from sensory cortical areas, how these sensory signals are processed remains unclear. Here we found that neurons in the caudal-ventral part of the putamen (putamen tail) process visual information including spatial and object features. These neurons discriminate many objects, first by their visual features and later by their reward values as well. Importantly, the value discrimination was based on long-term memory, but not on short-term memory. These results suggest that the putamen tail controls saccade/attention among objects with different historical values and might control other motor actions as well.

Amygdala activity for the modulation of goal-directed behavior in emotional contexts.

Choosing valuable objects and rewarding actions is critical for survival. While such choices must be made in a way that suits the animal's circumstances, the neural mechanisms underlying such context-appropriate behavior are unclear. To address this question, we devised a context-dependent reward-seeking task for macaque monkeys. Each trial started with the appearance of one of many visual scenes containing two or more objects, and the monkey had to choose the good object by saccade to get a reward. These scenes were categorized into two dimensions of emotional context: dangerous versus safe and rich versus poor. We found that many amygdala neurons were more strongly activated by dangerous scenes, by rich scenes, or by both. Furthermore, saccades to target objects occurred more quickly in dangerous than in safe scenes and were also quicker in rich than in poor scenes. Thus, amygdala neuronal activity and saccadic reaction times were negatively correlated in each monkey. These results suggest that amygdala neurons facilitate targeting saccades predictably based on aspects of emotional context, as is necessary for goal-directed and social behavior.

Functional properties of parietal hand manipulation-related neurons and mirror neurons responding to vision of own hand action.

Parietofrontal pathways play an important role in visually guided motor control. In this pathway, hand manipulation-related neurons in the inferior parietal lobule represent 3-D properties of an object and motor patterns to grasp it. Furthermore, mirror neurons show visual responses that are concerned with the actions of others and motor-related activity during execution of the same grasping action. Because both of these categories of neurons integrate visual and motor signals, these neurons may play a role in motor control based on visual feedback signals. The aim of this study was to investigate whether these neurons in inferior parietal lobule including the anterior intraparietal area and PFG of macaques represent visual images of the monkey's own hand during a self-generated grasping action. We recorded 235 neurons related to hand manipulation tasks. Of these, 54 responded to video clips of the monkey's own hand action, the same as visual feedback during that action or clips of the experimenter's hand action in a lateral view. Of these 54 neurons, 25 responded to video clips of the monkey's own hand, even without an image of the target object. We designated these 25 neurons as "hand-type." Thirty-three of 54 neurons that were defined as mirror neurons showed visual responses to the experimenter's action and motor responses. Thirteen of these mirror neurons were classified as hand-type. These results suggest that activity of hand manipulation-related and mirror neurons in anterior intraparietal/PFG plays a fundamental role in monitoring one's own body state based on visual feedback.

[What mirror neurons have revealed: revisited].

The first paper on mirror neurons was published in 1992. In the span of over two decades since then, much knowledge about the relationship between social cognitive function and the motor control system has been accumulated. Direct matching of visual actions and their corresponding motor representations is the most important functional property of mirror neuron. Many studies have emphasized intrinsic simulation as a core concept for mirror neurons. Mirror neurons are thought to play a role in social cognitive function. However, the function of mirror neurons in the macaque remains unclear, because such cognitive functions are limited or lacking in macaque monkeys. It is therefore important to discuss these neurons in the context of motor function. Rizzolatti and colleagues have stressed that the most important function of mirror neurons in macaques is recognition of actions performed by other individuals. I suggest that mirror neurons in the Macaque inferior pariental lobule might be correlated with body schema. In the parieto-premotor network, matching of corollary discharge and actual sensory feedback is an essential neuronal operation. Recently, neurons showing mirror properties were found in some cortical areas outside the mirror neuron system. The current work would revisit the outcomes of mirror neuron studies to discuss the function of mirror neurons in the monkey.