Birth of Projection Neurons in Adult Avian Brain May Be Related to Perceptual or Motor Learning

AbstractTuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder in which patients frequently present with autism spectrum disorder (ASD). A core diagnostic criterion for ASD is the presence of restricted, repetitive behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning, action selection and habit formation. Striatal control over motor behavior relies on the coordinated activity of two subtypes of principle neurons, direct pathway and indirect pathway spiny projection neurons (dSPNs or iSPNs, respectively), which provide the main output of the striatum. To test if altered striatal activity is sufficient to cause changes to motor behavior in the context of TSC, we conditionally deleted Tsc1 from dSPNs or iSPNs in mice and determined the consequences on synaptic function and motor learning. We find that mice with loss of Tsc1 from dSPNs, but not iSPNs, have enhanced motor routine learning in the accelerating rotarod task. In addition, dSPN Tsc1 KO mice have impaired endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses in the dorsal striatum. Consistent with a loss of eCB-LTD, disruption of Tsc1 in dSPNs, but not iSPNs, results in a strong enhancement of corticostriatal synaptic drive. Together these findings demonstrate that within the striatum, dSPNs show selective sensitivity to Tsc1 loss and indicate that enhanced cortical activation of the striatal direct pathway is a potential contributor to altered motor behaviors in TSC.

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Inhibition of cholinergic interneurons potentiates corticostriatal transmission in D1 receptor-expressing medium-sized spiny neurons and restores motor learning in parkinsonian condition

10.1101/2021.07.07.451477 ◽

2021 ◽

Author(s):

Gwenaelle Laverne ◽

Jonathan Pesce ◽

Ana Reynders ◽

Christophe Melon ◽

Lydia Kerkerian-Le Goff ◽

...

Keyword(s):

Motor Learning ◽

Long Term Potentiation ◽

D1 Receptor ◽

Skill Learning ◽

D1 Receptors ◽

Projection Neurons ◽

Cholinergic Interneurons ◽

Term Potentiation ◽

The Impact

Striatal cholinergic interneurons (CINs) respond to salient or reward prediction-related stimuli after conditioning with brief pauses in their activity, implicating them in learning and action selection. This pause is lost in animal models of Parkinson′s disease. How this signal regulates the functioning of the striatum remains an open question. To address this issue, we examined the impact of CIN firing inhibition on glutamatergic transmission between the cortex and the medium-sized spiny projection neurons expressing dopamine D1 receptors (D1 MSNs). Brief interruption of CIN activity had no effect in control condition whereas it increased glutamatergic responses in D1 MSNs after nigrostriatal dopamine denervation. This potentiation was dependent upon M4 muscarinic receptor and protein kinase A. Decreasing CIN firing by opto/chemogenetic strategies in vivo rescued long-term potentiation in some MSNs and alleviated motor learning deficits in parkinsonian mice. Taken together, our findings demonstrate that the control exerted by CINs on corticostriatal transmission and striatal-dependent motor-skill learning depends on the integrity of dopaminergic inputs.

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Pathogenic LRRK2 R1441C mutation is associated with striatal alterations

10.1101/2020.03.11.986455 ◽

2020 ◽

Cited By ~ 1

Author(s):

Harry S. Xenias ◽

Chuyu Chen ◽

Shuo Kang ◽

Suraj Cherian ◽

Xiaolei Situ ◽

...

Keyword(s):

Motor Learning ◽

Kinase Inhibitor ◽

Treatment Strategies ◽

Projection Neurons ◽

Indirect Pathway ◽

Behavioral Alterations ◽

Striatal Projection Neurons ◽

Lrrk2 Kinase ◽

The Impact ◽

Striatal Function

AbstractLRRK2 mutations are associated with both familial and sporadic forms of Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 plays critical roles in regulating striatal function. Here, by using knock-in mouse lines that express the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how pathogenic LRRK2 mutations altered striatal physiology. We found that R1441C mice displayed a reduced nigrostriatal dopamine release and hypoexcitability in indirect-pathway striatal projection neurons. These alterations were associated with an impaired striatal-dependent motor learning. This deficit in motor learning was rescued following the subchronic administration of the LRRK2 kinase inhibitor Mli-2. In contrast, though a decreased release of dopamine was observed in the G2019S knock-in mice no concomitant cellular and behavioral alterations were found. In summary, our data argue that the impact of LRRK2 mutations cannot be simply generalized. Our findings offer mechanistic insights for devising treatment strategies for PD patients.

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Emergence of stable striatal D1R and D2R neuronal ensembles with distinct firing sequence during motor learning

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1901712116 ◽

2019 ◽

Vol 116 (22) ◽

pp. 11038-11047 ◽

Cited By ~ 13

Author(s):

Meng-jun Sheng ◽

Di Lu ◽

Zhi-ming Shen ◽

Mu-ming Poo

Keyword(s):

Motor Learning ◽

Motor Behavior ◽

D2 Receptor ◽

Neuronal Population ◽

Projection Neurons ◽

Motor Tasks ◽

Neuronal Ensembles ◽

Two Photon ◽

Procedure Learning ◽

Sequential Firing

The dorsolateral striatum (DLS) is essential for motor and procedure learning, but the role of DLS spiny projection neurons (SPNs) of direct and indirect pathways, as marked, respectively, by D1 and D2 receptor (D1R and D2R) expression, remains to be clarified. Long-term two-photon calcium imaging of the same neuronal population during mouse learning of a cued lever-pushing task revealed a gradual emergence of distinct D1R and D2R neuronal ensembles that reproducibly fired in a sequential manner, with more D1R and D2R neurons fired during the lever-pushing period and intertrial intervals (ITIs), respectively. This sequential firing pattern was specifically associated with the learned motor behavior, because it changed markedly when the trained mice performed other cued motor tasks. Selective chemogenetic silencing of D1R and D2R neurons impaired the initiation of learned motor action and suppression of erroneous lever pushing during ITIs, respectively. Thus, motor learning involves reorganization of DLS neuronal activity, forming stable D1R and D2R neuronal ensembles that fired sequentially to regulate different aspects of the learned behavior.

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