Striatum-projecting prefrontal cortex neurons support working memory maintenance

Chernysheva, Maria; Sych, Yaroslav; Fomins, Aleksejs; Warren, José Luis Alatorre; Lewis, Chris; Capdevila, Laia Serratosa; Boehringer, Roman; Amadei, Elizabeth A.; Grewe, Benjamin F.; O’Connor, Eoin C.; Hall, Benjamin J.; Helmchen, Fritjof

doi:10.1101/2021.12.03.471159

Cited by 5 publications

(4 citation statements)

References 60 publications

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“…Previous studies suggested that the loops from the cortex through the basal ganglia could play a role in the maintenance of persistent activity for working memory (Wang, 2001; Wang et al, 2021). In accordance with this view, the nuclei of the basal ganglia are connected with frontal cortical regions that exhibit persistent activity during working-memory tasks (Saunders et al, 2015) and striatum-projecting neurons in the medial prefrontal cortex contribute to the maintenance of spatial working memories (Chernysheva et al, 2021). Furthermore, neurons of the basal ganglia themselves exhibit persistent activity during working memory tasks (Hikosaka and Wurtz, 1983; Hikosaka et al, 1989; Mushiake and Strick, 1995).…”

Section: Introductionmentioning

confidence: 77%

The direct and indirect pathways of the basal ganglia antagonistically influence cortical activity and perceptual decisions

Beest

Abdelwahab

Cazemier

et al. 2022

Preprint

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The striatum, input nucleus of the basal ganglia, receives topographically organized input from the cortex and gives rise to the direct and indirect pathways with antagonistic effects on the output of the basal ganglia. We optogenetically stimulated the direct and indirect pathways in mice and measured their influence on perceptual decisions and neuronal activity in the cortex. In a task in which mice had to detect a visual stimulus, unilateral direct-pathway stimulation increased the probability of lick responses to the non-stimulated side and increased cortical activity globally. In contrast, indirect-pathway stimulation increased the probability of licks to the stimulated side and decreased activity in visual cortical areas. To probe the possible role of the two pathways in working memory, we trained the mice to report the location of a stimulus with licking one of two spouts, after a memory delay. Direct-pathway stimulation prior to and during the memory delay enhanced both the neural representation of a contralateral visual stimulus and the number of contraversive choices, whereas indirect-pathway stimulation had the opposite effects, in accordance with an antagonistic influence of the direct and indirect pathways on licking direction. Our results demonstrate how these two pathways influence perceptual decisions and working memories, and modify activity in the cerebral cortex.

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Section: Introductionmentioning

confidence: 77%

The direct and indirect pathways of the basal ganglia antagonistically influence cortical activity and perceptual decisions

Beest

Abdelwahab

Cazemier

et al. 2022

Preprint

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“…Furthermore, the DS is both directly and indirectly connected to the brain structures most implicated in cognitive and social function. For instance, inhibiting DMS-projecting mPFC neurons during the delay period of a T-maze working memory task impairs performance, and DMS neurons are sequentially active during this delay period (13, 38). The DS is also connected through basal ganglia outputs to the thalamocortical connections thought to sustain persistent activity in the PFC during delay periods of working memory (20, 39).…”

Section: Discussionmentioning

confidence: 99%

Selective Nigrostriatal Dopamine Excess Impairs Behaviors Linked to the Cognitive and Negative Symptoms of Psychosis

Moya

Yun

Fleps

et al. 2022

Preprint

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BACKGROUND: Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work for positive symptoms by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms. Further, broadly increasing dopamine release improves cognitive function. These observations fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms, but this has never been tested with dopamine pathway specificity. METHODS: We selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of male and female Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively ac-tivate these neurons, validated this approach with fiber photometry, and assessed its effects on social and cogni-tive function. We combined this manipulation with antipsychotic treatment (haloperidol) and compared the path-way-specific manipulation to treatment with the non-selective dopamine releaser amphetamine. RESULTS: Selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired behavioral processes linked to negative and cognitive symptoms (social drive and working memory). Haloperidol normalized locomo-tion, only partially rescued working memory, and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. CONCLUSIONS: Excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Previous studies using non-selective approaches to release dopamine likely overlooked these contributions of excess dopamine to psychosis. Future therapies should address this disre-garded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.

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“…Wang, 2001;Wang et al, 2021). Consistent with this view, the nuclei of the basal ganglia are connected with frontal cortical regions that exhibit persistent activity during working-memory tasks(Saunders et al, 2015) and striatum-projecting neurons in the medial prefrontal cortex contribute to the maintenance of spatial working memories(Chernysheva et al, 2021). Furthermore, neurons of the basal ganglia themselves exhibit persistent activity during working memory tasks(Hikosaka and Wurtz, 1983;Hikosaka et al, 1989;Mushiake and Strick, 1995).On top of the anatomical organization, the basal ganglia contains separate pathways.The cerebral cortex projects to GABAergic neurons in the striatum that belong to the direct and indirect pathways (Figure 4.1B) and express different dopamine receptors.…”

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confidence: 70%

“…Consistent with torsion measurements in freely moving rats(Wallace et al, 2013), we found that torsion in mice was approximately linearly related to head pitch with a value of around 0.325 (FigureS2.8A).This value was used in all analyses.The distribution of left/right focea locations (Figure2.8B, FigureS2.8B) was computed using a grid of equally-spaced points in spherical coordinates (spacing 1°). The radius of the sphere was 10cm Ref 27. and the head of the animal was placed at the center of the sphere (nose pointing at ele=0° and azi=0°).…”

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confidence: 99%

Keep your eyes on the prize

van Beest

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In this thesis I aim to address the different components of visually driven goal-directed behavior, to understand how the brain can “keep an eye on the prize”. I use the mouse as a model system for the following reasons: 1) the main components of the mouse and human brain are similar, 2) we can make use of genetic tools in order to disentangle circuits involved in goal-directed behavior more specifically, and 3) the small size of the mouse brain makes it easier to visualize many cortical areas simultaneously, which is especially an advantage in tasks involving sensory input (posterior areas) as well as motor action (frontal areas). In Chapter 1 I introduce the (mouse) visual system and the concept that visual perception is modulated by context. I also introduce working memory as persistent activity during a delay, and how this is likely an emergent property of distributed functional networks. In addition, I explain how the basal ganglia are ideally suited to take up an orchestrating role as part of these functional networks. In Chapter 2 ”Mouse visual cortex contains a region of enhanced spatial resolution”, my colleagues and I reveal that despite the absence of a fovea in the retina, aspects of the organization of the visual cortex of mice resemble the foveal organization seen in primate visual cortex. We describe a region with enhanced spatial resolution in the visual cortex (‘focea’) which is behaviorally relevant: the mouse can see sharper with the focea. These findings have important implications for using the mouse as a model for human visual perception. In Chapter 3 “The essential role of recurrent processing for figure-ground perception in mice”, we find evidence that feedback signals from higher to lower visual areas are important to provide the visual context to cells with smaller receptive fields. This is useful, for example, for segregating a figure from a similar background. When this feedback signal is disturbed, both the neural correlate for separating figures from a background in the brain as well as figure detection performance decrease. In Chapter 4 "The direct and indirect pathways of the basal ganglia antagonistically influence cortical activity and perceptual decisions”, we first confirm that the two pathways of the basal ganglia can antagonistically bias motor responses and cortical activity in a visual detection task. We then demonstrate in a similar task with a delay between the sensory input and motor action that the basal ganglia also antagonistically bias the working memory of visual input and motor actions in the future. In the same task, we also observe interesting neuronal correlates of task parameters after a trial has finished. From computational models we know that these correlates, known as eligibility traces, are important for learning: they can be used to assign credit (or blame) after an outcome. Hence, we decided to investigate these possible eligibility traces further in Chapter 5 “Post-trial representations of task events throughout the dorsal cortex are modulated by behavioral context”. Altogether, this thesis adds relevant and new information to the process of visually driven goal-directed behavior. I propose that the cortex functions like an orchestra, with the basal ganglia as its conductor. New developments in systems neuroscience will enable large-scale recordings of individual neurons and neurotransmitters to further decipher if this is indeed how the brain manages to behave in a goal-directed way and keep an eye on the prize.

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Striatum-projecting prefrontal cortex neurons support working memory maintenance

Cited by 5 publications

References 60 publications

The direct and indirect pathways of the basal ganglia antagonistically influence cortical activity and perceptual decisions

The direct and indirect pathways of the basal ganglia antagonistically influence cortical activity and perceptual decisions

Selective Nigrostriatal Dopamine Excess Impairs Behaviors Linked to the Cognitive and Negative Symptoms of Psychosis

Keep your eyes on the prize

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