Dopaminergic organization of striatum is linked to cortical activity and brain expression of genes associated with psychiatric illness

McCutcheon, Robert; Brown, Kirsten; Nour, Matthew M.; Smith, Stephen M.; Veronese, Mattia; Zelaya, Fernando; Osugo, Martin; Jauhar, Sameer; Hallett, William A.; Mehta, Mitul; Howes, Oliver

doi:10.1126/sciadv.abg1512

Cited by 18 publications

(16 citation statements)

References 86 publications

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“…It is also worth noting that this study found the highest degree of amphetamine-induced dopamine release in the limbic striatum, contrary to more recent studies [45]. The neuromodulatory effects of dopamine signaling from the striatum are shown to affect distal cortical regions [176][177][178][179]. These findings highlight the key role of the corticostriatal circuitry in the regulation of functional brain networks.…”

Section: Correspondence With In Vivo Dwi and Functional Imaging Studiescontrasting

confidence: 94%

A new cortical parcellation based on systematic review of primate anatomical tracing studies on corticostriatal projections

Dinh

Nerland

Maximov

et al. 2022

Preprint

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Corticostriatal projections form the input level of a circuitry that connects the cerebral cortex, basal ganglia, and thalamus. Three distinct, functional subcircuits exist according to the tripartite model: Sensorimotor cortices projecting mainly to the dorsolateral striatum; associative cortices projecting to the dorsomedial striatum and limbic cortices projecting to the ventral striatum. However, there is to date no atlas that allows researchers to label cortical projection areas belonging to each of these subcircuits separately. To address this research gap, the aim of this study was threefold: First, to systematically review anatomical tracing studies that focused on corticostriatal projections in non-human primates, and to classify their findings according to the tripartite model. Second, to develop an atlas of the human cerebral cortex based on this classification. Third, to test the hypothesis that labels in this atlas show structural connectivity with specific striatal subregions in humans using diffusion-based tractography in a sample of 24 healthy participants. In total, 98 studies met the inclusion criteria for our systematic review. Information about projections from the cortex to the striatum was systematically extracted by Brodmann area, and cortical areas were classified by their dominant efferent projections. Taking known homological and functional similarities and differences between non-human primate and human cortical regions into account, a new human corticostriatal projection (CSP) atlas was developed. Using human diffusion-based tractography analyses, we found that the limbic and sensorimotor atlas labels showed preferential structural connectivity with the ventral and dorsolateral striatum, respectively. However, the pattern of structural connectivity for the associative label showed the greatest degree of overlap with other labels. We provide this new atlas as a freely available tool for neuroimaging studies, where it allows for the first-time delineation of anatomically informed regions-of-interest to study functional subcircuits within the corticostriatal circuitry. This tool will enable specific investigations of subcircuits involved in the pathogenesis of neuropsychiatric illness such as schizophrenia and bipolar disorders.

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Section: Correspondence With In Vivo Dwi and Functional Imaging Studiescontrasting

confidence: 94%

A new cortical parcellation based on systematic review of primate anatomical tracing studies on corticostriatal projections

Dinh

Nerland

Maximov

et al. 2022

Preprint

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“…Intriguingly, TAAR1 has also been shown to impact pre-and post-synaptic glutamatergic neurotransmission in the striatum of rodent Parkinson's disease models [144]. The ability to regulate corticostriatal crosstalk is not only of relevance to Parkinson's disease, but also schizophrenia and other psychiatric disorders [145]. Moreover, TAAR1 may participate in glutamate clearance via modulation of the excitatory amino acid transporter 2 (EAAT2) [146,147].…”

Section: Development Of Synthetic Taar1 Ligandsmentioning

confidence: 99%

Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies

Dedic

Dworak

Zeni

et al. 2021

IJMS

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Trace amine-associated receptor 1 (TAAR1) has emerged as a promising therapeutic target for neuropsychiatric disorders due to its ability to modulate monoaminergic and glutamatergic neurotransmission. In particular, agonist compounds have generated interest as potential treatments for schizophrenia and other psychoses due to TAAR1-mediated regulation of dopaminergic tone. Here, we review unmet needs in schizophrenia, the current state of knowledge in TAAR1 circuit biology and neuropharmacology, including preclinical behavioral, imaging, and cellular evidence in glutamatergic, dopaminergic and genetic models linked to the pathophysiology of psychotic, negative and cognitive symptoms. Clinical trial data for TAAR1 drug candidates are reviewed and contrasted with antipsychotics. The identification of endogenous TAAR1 ligands and subsequent development of small-molecule agonists has revealed antipsychotic-, anxiolytic-, and antidepressant-like properties, as well as pro-cognitive and REM-sleep suppressing effects of TAAR1 activation in rodents and non-human primates. Ulotaront, the first TAAR1 agonist to progress to randomized controlled clinical trials, has demonstrated efficacy in the treatment of schizophrenia, while another, ralmitaront, is currently being evaluated in clinical trials in schizophrenia. Coupled with the preclinical findings, this provides a rationale for further investigation and development of this new pharmacological class for the treatment of schizophrenia and other psychiatric disorders.

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“…We sought to test this hypothesis by using combined PET-magnetic resonance (MR) imaging to simultaneously measure both NMDAR availability in the hippocampus and glutamate levels in the striatum. In addition, given the evidence to support the involvement of fronto-striatal interactions in schizophrenia (McCutcheon et al, 2021) and to assess the specificity of the relationship between hippocampal NMDAR and striatal glutamate, we included an exploratory analysis to determine whether there is an association between frontal NMDAR availability and striatal glutamate levels.…”

Section: The Association Between N-methyl-d-aspartate Receptor Availa...mentioning

confidence: 99%

“…Our finding that lower hippocampal NMDAR availability is associated with higher striatal glutamate levels provides further evidence that hippocampal dysfunction is linked to the function of the striatum in psychosis (Adams et al, 2020; Lieberman et al, 2018; Stone et al, 2010). However, it should be recognised that this does not preclude the involvement of other circuit dysfunction in the illness as well (McCutcheon et al, 2021).…”

Section: Interpretation and Implications For The Pathophysiology Of P...mentioning

confidence: 99%

The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls

et al. 2022

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Background: Evidence from post-mortem studies and in vivo imaging studies suggests there may be reduced N-methyl-d-aspartate receptor (NMDAR) levels in the hippocampus in patients with schizophrenia. Other studies have reported increased glutamate in striatum in schizophrenia patients. It has been hypothesised that NMDAR hypofunction leads to the disinhibition of glutamatergic signalling; however, this has not been tested in vivo. Methods: In this study, we investigated the relationship between hippocampal NMDAR and striatal glutamate using simultaneous positron emission tomography-magnetic resonance (PET-MR) imaging. We recruited 40 volunteers to this cross-sectional study; 21 patients with schizophrenia, all in their first episode of illness, and 19 healthy controls. We measured hippocampal NMDAR availability using the PET ligand [18F]GE179. This was indexed relative to whole brain as the distribution volume ratio (DVR). Striatal glutamatergic indices (glutamate and Glx) were acquired simultaneously, using combined PET-MR proton magnetic resonance spectroscopy (1H-MRS). Results: A total of 33 individuals (15 healthy controls, 18 patients) were included in the analyses (mean (SD) age of controls, 27.31 (4.68) years; mean (SD) age of patients, 24.75 (4.33), 27 male and 6 female). We found an inverse relationship between hippocampal DVR and striatal glutamate levels in people with first-episode psychosis (rho = −0.74, p < 0.001) but not in healthy controls (rho = −0.22, p = 0.44). Conclusion: This study show that lower relative NMDAR availability in the hippocampus may drive increased striatal glutamate levels in patients with schizophrenia. Further work is required to determine whether these findings may yield new targets for drug development in schizophrenia.

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Dopaminergic organization of striatum is linked to cortical activity and brain expression of genes associated with psychiatric illness

Cited by 18 publications

References 86 publications

A new cortical parcellation based on systematic review of primate anatomical tracing studies on corticostriatal projections

A new cortical parcellation based on systematic review of primate anatomical tracing studies on corticostriatal projections

Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies

The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls

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