Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction

Alabi, Opeyemi O.; Davatolhagh, M. Felicia; Robinson, Mara; Fortunato, Michael; Cifuentes, Luigim Vargas; Kable, Joseph W.; Fuccillo, Marc V.

doi:10.7554/elife.54838

Cited by 15 publications

(18 citation statements)

References 97 publications

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“…Finally, we also noted that PL::A-DMS inhibition disrupted the natural slowing of trial initiations observed following negative outcomes (Fig. 7f,h) 24,27,28 . These results support divergent fronto-striatal control of outcome-related strategies, with PL::P-DMS activity mediating positive reinforcement and PL::A-DMS driving choice persistence in the face of negative outcomes.…”

Section: Pl::dms Pathways Divergently Control Response Strategies To Positive and Negative Outcomessupporting

confidence: 58%

“…S7). To analyze effects on choice selection, we took advantage of the strong dependence on prior trial outcomes 27,28 , analyzing win-stay and lose-stay probabilities (see Methods). We found no evidence that optogenetic inhibition of PL::A-DMS throughout the choice period had any impact upon ongoing action selection (Fig.…”

Section: Pl::a-dms Pathways Mediate Future Choice Valuation But Not Current Choice Executionmentioning

confidence: 99%

“…Finally, we estimated internal value representations with a standard Q-learning model, which proved strongly predictive of future animal choice in our experiments (Fig. S2a,c) 27,28 . Latent variables inferred with the Q-learning scheme were included in the neural encoding model as predictors representing trial-by-trial choice values (DQ, SQ) and reward prediction errors (RPE+/-).…”

Section: Assessing Neural Activity In Pl::dms Pathways During a Goal-directed Choice Taskmentioning

confidence: 99%

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Distributed processing for action control by prelimbic circuits targeting anterior-posterior dorsal striatal subregions

Choi¹,

Piasini

Vargas

et al. 2021

Preprint

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Fronto-striatal circuits have been extensively implicated in the cognitive control of behavioral output for both social and appetitive rewards. The functional diversity of prefrontal cortical populations is strongly dependent on their synaptic targets, with control of motor output strongly mediated by connectivity to the dorsal striatum. Despite evidence for functional diversity along the anterior-posterior axis of the dorsomedial striatum (DMS), it is unclear how distinct fronto- striatal sub-circuits support neural computations essential for action selection. Here we identify prefrontal populations targeting distinct DMS subregions and characterize their functional roles. We first performed neural circuit tracing to reveal segregated prefrontal populations defined by anterior/posterior dorsomedial striatal target. We then probed the functional relevance of these parallel circuits via in vivo calcium imaging and temporally precise causal manipulations during a feedback-based 2-alternative choice task. Single-photon imaging revealed circuit-specific representations of task-relevant information with prelimbic neurons targeting anterior DMS (PL::A- DMS) uniquely encoded choices and responses to negative outcomes, while prelimbic neurons targeting posterior DMS (PL::P-DMS) encoded internal representations of value and positive outcomes contingent on prior choice. Consistent with this distributed coding, optogenetic inhibition of PL::A-DMS circuits strongly impacted choice monitoring and behavioral control in response to negative outcomes while perturbation of PL::P-DMS signals impaired task engagement and strategies following positive outcomes. Di-synaptic retrograde tracing uncovered differences in afferent connectivity that may underlie these pathways functional divergence. Together our data uncover novel PL populations engaged in distributed processing for action control.SUMMARYPrelimbic cortex engages A- and P-DMS via distinct circuitsPL::A-DMS and PL::P-DMS pathways encode divergent aspects of a simple goal-directed taskPL::A-DMS pathways shape responding to negative outcomes via multiple mechanismsPL::P-DMS pathways guide engagement and choices in response to positive outcomesAfferent connectomes of PL neurons defined by A-P DMS target are distinct

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Section: Pl::dms Pathways Divergently Control Response Strategies To Positive and Negative Outcomessupporting

confidence: 58%

Section: Pl::a-dms Pathways Mediate Future Choice Valuation But Not Current Choice Executionmentioning

confidence: 99%

Section: Assessing Neural Activity In Pl::dms Pathways During a Goal-directed Choice Taskmentioning

confidence: 99%

See 1 more Smart Citation

Distributed processing for action control by prelimbic circuits targeting anterior-posterior dorsal striatal subregions

Choi¹,

Piasini

Vargas

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Nevertheless, this selective decrease in cortical-iSPN excitatory drive is expected to promote disinhibition of thalamic structures projecting back to the cortex. It is an interesting future question as to whether this thalamic disinhibition can explain both simple motor phenotypes (e.g., hyperactivity, aggression) ( Etherton et al, 2009 ; Grayton et al, 2013 ) and more complex reward-processing deficits observed in mice with Nrxn1α mutations ( Alabi et al, 2020 ). It is worth noting a recent study of the Tsc1 deletion ASD mouse model, which exhibited increased corticostriatal connectivity selectively onto dSPNs, with synaptic strength unperturbed at thalamostriatal synapses ( Benthall et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Neurexin1⍺ differentially regulates synaptic efficacy within striatal circuits

Davatolhagh

Fuccillo

2021

Cell Reports

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SUMMARY Mutations in genes essential for synaptic function, such as the presynaptic adhesion molecule Neurexin1α (Nrxn1α), are strongly implicated in neuropsychiatric pathophysiology. As the input nucleus of the basal ganglia, the striatum integrates diverse excitatory projections governing cognitive and motor control, and its impairment may represent a recurrent pathway to disease. Here, we test the functional relevance of Nrxn1α in striatal circuits by employing optogenetic-mediated afferent recruitment of dorsal prefrontal cortical (dPFC) and parafascicular thalamic connections onto dorsomedial striatal (DMS) spiny projection neurons (SPNs). For dPFC-DMS circuits, we find decreased synaptic strength specifically onto indirect pathway SPNs in both Nrxn1α +/− and Nrxn1α −/− mice, driven by reductions in neurotransmitter release. In contrast, thalamic excitatory inputs to DMS exhibit relatively normal excitatory synaptic strength despite changes in synaptic N -methyl-D-aspartate receptor (NMDAR) content. These findings suggest that dysregulation of Nrxn1α modulates striatal function in an input- and target-specific manner.

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“…Furthermore, they show stereotypic and repetitive behaviors such as increased grooming, impaired nest-building, altered novelty responsiveness, and habituation [ 31 , 35 , 38 ]. In addition, several behaviors were reported that relate to ASD comorbidities including deficits in learning and cognition, locomotor activity, motor performance, award processing, and anxiety-like behaviors [ 31 , 35 , 36 , 38 , 46 , 47 , 48 , 49 ]. Although the social, stereotyped, and repetitive behaviors are commonly studied, sensory behaviors have received less attention in this model.…”

Section: From Human Asd Genetics To Translational Behavioral Phenotype In Mouse Modelsmentioning

confidence: 99%

Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

Riemersma

Havekes

Kas

2021

Genes

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Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by differences in social interaction, repetitive behaviors, restricted interests, and sensory differences beginning early in life. Especially sensory symptoms are highly correlated with the severity of other behavioral differences. ASD is a highly heterogeneous condition on multiple levels, including clinical presentation, genetics, and developmental trajectories. Over a thousand genes have been implicated in ASD. This has facilitated the generation of more than two hundred genetic mouse models that are contributing to understanding the biological underpinnings of ASD. Since the first symptoms already arise during early life, it is especially important to identify both spatial and temporal gene functions in relation to the ASD phenotype. To further decompose the heterogeneity, ASD-related genes can be divided into different subgroups based on common functions, such as genes involved in synaptic function. Furthermore, finding common biological processes that are modulated by this subgroup of genes is essential for possible patient stratification and the development of personalized early treatments. Here, we review the current knowledge on behavioral rodent models of synaptic dysfunction by focusing on behavioral phenotypes, spatial and temporal gene function, and molecular targets that could lead to new targeted gene-based therapy.

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Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction

Cited by 15 publications

References 97 publications

Distributed processing for action control by prelimbic circuits targeting anterior-posterior dorsal striatal subregions

Distributed processing for action control by prelimbic circuits targeting anterior-posterior dorsal striatal subregions

Neurexin1⍺ differentially regulates synaptic efficacy within striatal circuits

Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

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