Striosomes Mediate Value-Based Learning Vulnerable in Age and a Huntington’s Disease Model

Friedman, Alexander; Hueske, Emily; Drammis, Sabrina; Arana, Sebastian E. Toro; Nelson, Erik D.; Carter, Cody W.; Delcasso, Sebastien; Rodriguez, Raimundo X.; Lutwak, Hope; DiMarco, Kaden S.; Zhang, Qingyang; Rakocevic, Lara; Hu, Dan; Xiong, Joshua; Zhao, Jinjing; Gibb, Leif; Yoshida, Tomoko; Siciliano, Cody A.; Diefenbach, Thomas; Ramakrishnan, Charu; Deisseroth, Karl; Graybiel, Ann M.

doi:10.1016/j.cell.2020.09.060

Cited by 41 publications

(54 citation statements)

References 117 publications

(105 reference statements)

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“…Further experiments strongly implicated a local intrastriatal circuit as being the switching mechanism ( Friedman et al, 2015 , 2017 , 2020 ). The circuit, to our current estimation, controls by fine-resolution temporal dynamics the relative time of arrival of cortical commands to the striosomal projection neurons and their inputs from the implicated interneurons, also innervated by the cortical circuit.…”

Section: The Pacc-striosomal Circuit and Its Involvement In Pessimistic Decision-makingmentioning

confidence: 96%

“…Thus again, abnormal value judgment under conditions of Ap-Av conflict occurred, and now could be causally associated with the cortico-striosomal system and its local circuit modulation ( Friedman et al, 2017 ). New work ( Friedman et al, 2020 ) has now extended the functional study of this pathway to address its potential role in value-based learning involving valence discrimination and in the ability to engage in tasks. With chemogenetics, our group found that a motivational state characterized by the level of task engagement could be causally influenced by levels of striosome-predominant activity in contrast to a lack of such an effect by matrix-predominant activity.…”

Section: The Pacc-striosomal Circuit and Its Involvement In Pessimistic Decision-makingmentioning

confidence: 99%

“…Optogenetically induced activation of matrix neurons elicited an increase in choices to approach large-reward outcomes neglecting their high cost ( Friedman et al, 2017 ). Further, striosomal activity was shaped in coordination with valence-based learning, in contrast to a lack of such correlated activity in the matrix compartment ( Friedman et al, 2020 ). Thus the striosome compartment of the striatum could be essential for learning about the values of good and bad outcomes of decisions, whereas the matrix could process the value of actions.…”

Section: Hypothesesmentioning

confidence: 99%

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Causal Evidence for Induction of Pessimistic Decision-Making in Primates by the Network of Frontal Cortex and Striosomes

2021

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Clinical studies have shown that patients with anxiety disorders exhibited coactivation of limbic cortices and basal ganglia, which together form a large-scale brain network. The mechanisms by which such a large-scale network could induce or modulate anxiety-like states are largely unknown. This article reviews our experimental program in macaques demonstrating a causal involvement of local striatal and frontal cortical sites in inducing pessimistic decision-making that underlies anxiety. Where relevant, we related these findings to the wider literature. To identify such sites, we have made a series of methodologic advances, including the combination of causal evidence for behavioral modification of pessimistic decisions with viral tracing methods. Critically, we introduced a version of the classic approach-avoidance (Ap-Av) conflict task, modified for use in non-human primates. We performed microstimulation of limbic-related cortical regions and the striatum, focusing on the pregenual anterior cingulate cortex (pACC), the caudal orbitofrontal cortex (cOFC), and the caudate nucleus (CN). Microstimulation of localized sites within these regions induced pessimistic decision-making by the monkeys, supporting the idea that the focal activation of these regions could induce an anxiety-like state, which subsequently influences decision-making. We further performed combined microstimulation and tract-tracing experiments by injecting anterograde viral tracers into focal regions, at which microstimulation induced increased avoidance. We found that effective stimulation sites in both pACC and cOFC zones projected preferentially to striosomes in the anterior striatum. Experiments in rodents have shown that the striosomes in the anterior striatum project directly to the dopamine-containing cells in the substantia nigra, and we have found evidence for a functional connection between striosomes and the lateral habenular region in which responses to reward are inhibitory. We present here further evidence for network interactions: we show that the pACC and cOFC project to common structures, including not only the anterior parts of the striosome compartment but also the tail of the CN, the subgenual ACC, the amygdala, and the thalamus. Together, our findings suggest that networks having pACC and cOFC as nodes share similar features in their connectivity patterns. We here hypothesize, based on these results, that the brain sites related to pessimistic judgment are mediated by a large-scale brain network that regulates dopaminergic functions and includes striosomes and striosome-projecting cortical regions.

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Section: The Pacc-striosomal Circuit and Its Involvement In Pessimistic Decision-makingmentioning

confidence: 96%

Section: The Pacc-striosomal Circuit and Its Involvement In Pessimistic Decision-makingmentioning

confidence: 99%

Section: Hypothesesmentioning

confidence: 99%

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Causal Evidence for Induction of Pessimistic Decision-Making in Primates by the Network of Frontal Cortex and Striosomes

2021

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“…Importantly, Friedman and colleagues [42] found a correlation between the activity of the striosomal populations and the valence discriminations achieved by the mice, and these signals and correlations were sensitive to motivational value, as tested by outcome devaluation. Collectively, this and previous studies of striosomal function [41,42] suggest that striosomes could serve as a subjective value filter via integration of cortical task information and motivational state on route to the DA system.…”

Section: The Cb1 Crosstalk With the Striosomal Activity On The Molecumentioning

confidence: 98%

“…The corticolimbic DA circuit, with excitatory glutamatergic projections from the medial prefrontal cortex to the basal ganglia, is involved in motivational processes, assignment of reward and cost value [41] and in valence, including subjective value [42] It is susceptible to psychosocial stress [43], which, in turn, is a major trigger for the onset, occurrence and reoccurrence of many psychopathologies including major depression. DA transmission is essential for attribution of incentive salience [44] and prediction of reward occurrence [45].…”

Section: Dopamine and Major Depression 21 Location Of Da Activity Wmentioning

confidence: 99%

Discovering the Lost Reward: Critical Locations for Endocannabinoid Modulation of the Cortico–Striatal Loop That Are Implicated in Major Depression

Ferber

Weller

Yadid

et al. 2021

IJMS

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Depression, the most prevalent psychiatric disorder in the Western world, is characterized by increased negative affect (i.e., depressed mood, cost value increase) and reduced positive affect (i.e., anhedonia, reward value decrease), fatigue, loss of appetite, and reduced psychomotor activity except for cases of agitative depression. Some forms, such as post-partum depression, have a high risk for suicidal attempts. Recent studies in humans and in animal models relate major depression occurrence and reoccurrence to alterations in dopaminergic activity, in addition to other neurotransmitter systems. Imaging studies detected decreased activity in the brain reward circuits in major depression. Therefore, the location of dopamine receptors in these circuits is relevant for understanding major depression. Interestingly, in cortico–striatal–dopaminergic pathways within the reward and cost circuits, the expression of dopamine and its contribution to reward are modulated by endocannabinoid receptors. These receptors are enriched in the striosomal compartment of striatum that selectively projects to dopaminergic neurons of substantia nigra compacta and is vulnerable to stress. This review aims to show the crosstalk between endocannabinoid and dopamine receptors and their vulnerability to stress in the reward circuits, especially in corticostriatal regions. The implications for novel treatments of major depression are discussed.

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DARPP‐32 cells and neuropil define striosomal system and isolated matrix cells in human striatum

Arasaratnam

Song

Yoshida

et al. 2023

J of Comparative Neurology

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The dorsal striatum forms a central node of the basal ganglia interconnecting the neocortex and thalamus with circuits modulating mood and movement. Striatal projection neurons (SPNs) include relatively intermixed populations expressing D1‐type or D2‐type dopamine receptors (dSPNs and iSPNs) that give rise to the direct (D1) and indirect (D2) output systems of the basal ganglia. Overlaid on this organization is a compartmental organization, in which a labyrinthine system of striosomes made up of sequestered SPNs is embedded within the larger striatal matrix. Striosomal SPNs also include D1‐SPNs and D2‐SPNs, but they can be distinguished from matrix SPNs by many neurochemical markers. In the rodent striatum the key signaling molecule, DARPP‐32, is a exception to these compartmental expression patterns, thought to befit its functions through opposite actions in both D1‐ and D2‐expressing SPNs. We demonstrate here, however, that in the dorsal human striatum, DARPP‐32 is concentrated in the neuropil and SPNs of striosomes, especially in the caudate nucleus and dorsomedial putamen, relative to the matrix neuropil in these regions. The generally DARPP‐32‐poor matrix contains scattered DARPP‐32‐positive cells. DARPP‐32 cell bodies in both compartments proved negative for conventional intraneuronal markers. These findings raise the potential for specialized DARPP‐32 expression in the human striosomal system and in a set of DARPP‐32‐positive neurons in the matrix. If DARPP‐32 immunohistochemical positivity predicts differential functional DARPP‐32 activity, then the distributions demonstrated here could render striosomes and dispersed matrix cells susceptible to differential signaling through cAMP and other signaling systems in health and disease. DARPP‐32 is highly concentrated in cells and neuropil of striosomes in post‐mortem human brain tissue, particularly in the dorsal caudate nucleus. Scattered DARPP‐32‐positive cells are found in the human striatal matrix. Calbindin and DARPP‐32 do not colocalize within every spiny projection neuron in the dorsal human caudate nucleus.

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Striosomes Mediate Value-Based Learning Vulnerable in Age and a Huntington’s Disease Model

Cited by 41 publications

References 117 publications

Causal Evidence for Induction of Pessimistic Decision-Making in Primates by the Network of Frontal Cortex and Striosomes

Causal Evidence for Induction of Pessimistic Decision-Making in Primates by the Network of Frontal Cortex and Striosomes

Discovering the Lost Reward: Critical Locations for Endocannabinoid Modulation of the Cortico–Striatal Loop That Are Implicated in Major Depression

DARPP‐32 cells and neuropil define striosomal system and isolated matrix cells in human striatum

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