Dopamine neurons are thought to be critical for reward value-based learning by modifying synaptic transmissions in the striatum. Yet, different regions of the striatum seem to guide different kinds of learning. Do dopamine neurons contribute to the regional differences of the striatum in learning? As a first step to answer this question, we examined whether the head and tail of the caudate nucleus of the monkey (Macaca mulatta) receive inputs from the same or different dopamine neurons. We chose these caudate regions because we previously showed that caudate head neurons learn values of visual objects quickly and flexibly, whereas caudate tail neurons learn object values slowly but retain them stably. Here we confirmed the functional difference by recording single neuronal activity while the monkey performed the flexible and stable value tasks, and then injected retrograde tracers in the functional domains of caudate head and tail. The projecting dopaminergic neurons were identified using tyrosine hydroxylase immunohistochemistry. We found that two groups of dopamine neurons in the substantia nigra pars compacta project largely separately to the caudate head and tail. These groups of dopamine neurons were mostly separated topographically: head-projecting neurons were located in the rostral-ventral-medial region, while tail-projecting neurons were located in the caudal-dorsal-lateral regions of the substantia nigra. Furthermore, they showed different morphological features: tail-projecting neurons were larger and less circular than head-projecting neurons. Our data raise the possibility that different groups of dopamine neurons selectively guide learning of flexible (short-term) and stable (long-term) memories of object values. Gaze is strongly attracted to visual objects that have been associated with rewards. Key to this function is a basal ganglia circuit originating from the caudate nucleus (CD), mediated by the substantia nigra pars reticulata (SNr), and aiming at the superior colliculus (SC). Notably, subregions of CD encode values of visual objects differently: stably by CD tail CD(T) vs. flexibly by CD head CD(H). Are the stable and flexible value signals processed separately throughout the CD-SNr-SC circuit? To answer this question, we identified SNr neurons by their inputs from CD and outputs to SC and examined their sensitivity to object values. The direct input from CD was identified by SNr neurons inhibitory response to electrical stimulation of CD. We found that SNr neurons were separated into two groups: 1) neurons inhibited by CD(T) stimulation, located in the caudal-dorsal-lateral SNr (cdlSNr), and 2) neurons inhibited by CD(H) stimulation, located in the rostral-ventralmedial SNr (rvmSNr). Most of CD(T)-recipient SNr neurons encoded stable values, whereas CD(H)-recipient SNr neurons tended to encode flexible values. The output to SC was identified by SNr neurons antidromic response to SC stimulation. Among the antidromically activated neurons, many encoded only stable values, while some encoded only flexible values. These results suggest that CD(T)- cdlSNr-SC circuit and CD(H)-rvmSNr-SC circuit transmit stable and flexible value signals, largely separately, to SC. The speed of signal transmission was faster through CD(T)-cdlSNr-SC circuit than through CD(H)-rvmSNr-SC circuit, which may reflect automatic and controlled gaze orienting guided by these circuits. The basal ganglia control body movements, value processing and decision-making. Many studies have shown that the inputs and outputs of each basal ganglia structure are topographically organized, which suggests that the basal ganglia consist of separate circuits that serve distinct functions. A notable example is the circuits that originate from the rostral (head) and caudal (tail) regions of the caudate nucleus, both of which target the superior colliculus. These two caudate regions encode the reward values of visual objects differently: flexible (short-term) values by the caudate head and stable (long-term) values by the caudate tail. These value signals in the caudate guide the orienting of gaze differently: voluntary saccades by the caudate head circuit and automatic saccades by the caudate tail circuit. Moreover, separate groups of dopamine neurons innervate the caudate head and tail and may selectively guide the flexible and stable learning/memory in the caudate regions. Studies focusing on manual handling of objects also suggest that rostrocaudally separated circuits in the basal ganglia control the action differently. These results suggest that the basal ganglia contain parallel circuits for two steps of goal-directed behavior: finding valuable objects and manipulating the valuable objects. These parallel circuits may underlie voluntary behavior and automatic skills, enabling animals (including humans) to adapt to both volatile and stable environments. This understanding of the functions and mechanisms of the basal ganglia parallel circuits may inform the differential diagnosis and treatment of basal ganglia disorders. It has been suggested that the basal forebrain (BF) exerts strong influences on the formation of memory and behavior. However, what information is used for the memory-behavior formation is unclear. We found that a population of neurons in the medial BF (medial septum and diagonal band of Broca) of macaque monkeys encodes a unique combination of information: reward uncertainty, expected reward value, anticipation of punishment, and unexpected reward and punishment. The results were obtained while the monkeys were expecting (often with uncertainty) a rewarding or punishing outcome during a Pavlovian procedure, or unexpectedly received an outcome outside the procedure. In vivo anterograde tracing using manganese-enhanced MRI suggested that the major recipient of these signals is the intermediate hippocampal formation. Based on these findings, we hypothesize that the medial BF identifies various contexts and outcomes that are critical for memory processing in the hippocampal formation.

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Ghazizadeh, Ali; Hong, Simon; Hikosaka, Okihide (2018) Prefrontal Cortex Represents Long-Term Memory of Object Values for Months. Curr Biol 28:2206-2217.e5
Ghazizadeh, Ali; Griggs, Whitney; Leopold, David A et al. (2018) Temporal-prefrontal cortical network for discrimination of valuable objects in long-term memory. Proc Natl Acad Sci U S A 115:E2135-E2144
Griggs, Whitney S; Amita, Hidetoshi; Gopal, Atul et al. (2018) Visual Neurons in the Superior Colliculus Discriminate Many Objects by Their Historical Values. Front Neurosci 12:396
Maeda, Kazutaka; Kunimatsu, Jun; Hikosaka, Okihide (2018) Amygdala activity for the modulation of goal-directed behavior in emotional contexts. PLoS Biol 16:e2005339
Hikosaka, Okihide; Kim, Hyoung F; Amita, Hidetoshi et al. (2018) Direct and indirect pathways for choosing objects and actions. Eur J Neurosci :
Amita, Hidetoshi; Kim, Hyoung F; Smith, Mitchell K et al. (2018) Neuronal connections of direct and indirect pathways for stable value memory in caudal basal ganglia. Eur J Neurosci :
Kim, Hyoung F; Amita, Hidetoshi; Hikosaka, Okihide (2017) Indirect Pathway of Caudal Basal Ganglia for Rejection of Valueless Visual Objects. Neuron 94:920-930.e3
Hikosaka, Okihide; Ghazizadeh, Ali; Griggs, Whitney et al. (2017) Parallel basal ganglia circuits for decision making. J Neural Transm (Vienna) :
Griggs, Whitney S; Kim, Hyoung F; Ghazizadeh, Ali et al. (2017) Flexible and Stable Value Coding Areas in Caudate Head and Tail Receive Anatomically Distinct Cortical and Subcortical Inputs. Front Neuroanat 11:106
Yasuda, Masaharu; Hikosaka, Okihide (2017) To Wait or Not to Wait-Separate Mechanisms in the Oculomotor Circuit of Basal Ganglia. Front Neuroanat 11:35

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