Optogenetic inhibition of indirect pathway neurons in the dorsomedial striatum reduces excessive grooming in Sapap3-knockout mice

Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive–compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.

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Depression in the Direct Pathway of the Dorsomedial Striatum Permits the Formation of Habitual Action

Cerebral Cortex ◽

10.1093/cercor/bhab031 ◽

2021 ◽

Author(s):

Xiaoxuan Yu ◽

Shijie Chen ◽

Qiang Shan

Keyword(s):

Synaptic Plasticity ◽

Dorsal Striatum ◽

Excitatory Synapses ◽

Indirect Pathway ◽

Optimal Outcomes ◽

Direct Pathway ◽

Parallel Circuits ◽

Directed Action ◽

Action Strategies ◽

Dorsomedial Striatum

Abstract In order to achieve optimal outcomes in an ever-changing environment, humans and animals generally manage their action control via either goal-directed action or habitual action. These two action strategies are thought to be encoded in distinct parallel circuits in the dorsal striatum, specifically, the posterior dorsomedial striatum (DMS) and the dorsolateral striatum (DLS), respectively. The striatum is primarily composed of two subtypes of medium spiny neurons (MSNs): the direct-pathway striatonigral and the indirect-pathway striatopallidal MSNs. MSN-subtype-specific synaptic plasticity in the DMS and the DLS has been revealed to underlie goal-directed action and habitual action, respectively. However, whether any MSN-subtype-specific synaptic plasticity in the DMS is associated with habitual action, and if so, whether the synaptic plasticity affects the formation of habitual action, are not known. This study demonstrates that postsynaptic depression in the excitatory synapses of the direct-pathway striatonigral MSNs in the DMS is formed after habit learning. Moreover, chemogenetically rescuing this depression compromises the acquisition, but not the expression, of habitual action. These findings reveal that an MSN-subtype-specific synaptic plasticity in the DMS affects habitual action and suggest that plasticity in the DMS as well as in the DLS contributes to the formation of habitual action.

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Striatal direct and indirect pathway neurons differentially control the encoding and updating of goal-directed learning

eLife ◽

10.7554/elife.58544 ◽

2020 ◽

Vol 9 ◽

Author(s):

James Peak ◽

Billy Chieng ◽

Genevra Hart ◽

Bernard W Balleine

Keyword(s):

Response Bias ◽

Projection Neurons ◽

Indirect Pathway ◽

Response Flexibility ◽

Directed Action ◽

Elevated Expression ◽

Directed Learning ◽

Series Of Experiments ◽

Dorsomedial Striatum

The posterior dorsomedial striatum (pDMS) is necessary for goal-directed action; however, the role of the direct (dSPN) and indirect (iSPN) spiny projection neurons in the pDMS in such actions remains unclear. In this series of experiments, we examined the role of pDMS SPNs in goal-directed action in rats and found that whereas dSPNs were critical for goal-directed learning and for energizing the learned response, iSPNs were involved in updating that learning to support response flexibility. Instrumental training elevated expression of the plasticity marker Zif268 in dSPNs only, and chemogenetic suppression of dSPN activity during training prevented goal-directed learning. Unilateral optogenetic inhibition of dSPNs induced an ipsilateral response bias in goal-directed action performance. In contrast, although initial goal-directed learning was unaffected by iSPN manipulations, optogenetic inhibition of iSPNs, but not dSPNs, impaired the updating of this learning and attenuated response flexibility after changes in the action-outcome contingency.

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Choice suppression is achieved through opponent but not independent function of the striatal indirect pathway in mice

10.1101/675850 ◽

2019 ◽

Author(s):

Kristen Delevich ◽

Benjamin Hoshal ◽

Anne GE Collins ◽

Linda Wilbrecht

Keyword(s):

Action Selection ◽

Projection Neurons ◽

Independent Function ◽

Indirect Pathway ◽

Successful Design ◽

Freely Moving ◽

Foraging Task ◽

Simple Fashion ◽

Dorsomedial Striatum

AbstractThe dorsomedial striatum (DMS) plays a key role in action selection, but little is known about how direct and indirect pathway spiny projection neurons (dSPNs and iSPNs) contribute to choice suppression in freely moving animals. Here, we used pathway-specific chemogenetic manipulation during a serial choice foraging task to test opposing predictions for iSPN function generated by two theories: 1) the ‘select/suppress’ heuristic which suggests iSPN activity is required to suppress alternate choices and 2) the network-inspired Opponent Actor Learning model (OpAL) which proposes that the weighted difference of dSPN and iSPN activity determines choice. We found that chemogenetic activation, but not inhibition, of iSPNs disrupted learned suppression of nonrewarded choices, consistent with the predictions of the OpAL model. Our findings suggest that iSPNs’ role in stopping and freezing does not extend in a simple fashion to choice suppression. These data may provide insights critical for the successful design of interventions for addiction or other conditions in which suppression of behavior is desirable.

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Excitatory synaptogenesis in the anterior cingulate cortex is required for effort/reward evaluation

10.1101/2021.04.20.440613 ◽

2021 ◽

Author(s):

Francesco Paolo Ulloa Severino ◽

Oluwadamilola Lawal ◽

Kristina Sakers ◽

Namsoo Kim ◽

Chaichontat Sriworarat ◽

...

Keyword(s):

Anterior Cingulate Cortex ◽

Knockout Mice ◽

Synapse Formation ◽

Cingulate Cortex ◽

Conditional Knockout ◽

Anterior Cingulate ◽

Neuronal Circuit ◽

Circuit Development ◽

And Performance ◽

Dorsomedial Striatum

AbstractSynaptogenesis is essential for circuit development; however, whether it is critical in adulthood for learning and performance of voluntary behaviors is unknown. Here we show that reward-based training in mice induces excitatory synapse formation onto Anterior Cingulate Cortex (ACC) neurons projecting to the dorsomedial striatum (DMS). We used germline and conditional knockout mice for Gabapentin/Thrombospondin receptor α2δ-1, which is required for excitatory synaptogenesis in the cortex, and found that loss of α2δ-1 in the adult ACC-DMS circuit is sufficient to abolish training-induced excitatory synaptogenesis. Surprisingly, this manipulation did not affect learning, instead caused a profound increase in effort exertion. Optogenetic activation of ACC-DMS neurons was sufficient to diminish effort exertion in wildtype mice and rescued the effort/reward evaluation deficit of the conditional α2δ-1 mutants. These results highlight the importance of synaptogenic signaling in the adult and pinpoint the ACC-DMS neuronal circuit as the controller of effort exertion during voluntary behaviors.

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Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice

10.1101/2021.06.01.446609 ◽

2021 ◽

Author(s):

Kristen Delevich ◽

Christopher D. Hall ◽

Linda Wilbrecht

Keyword(s):

Behavioral Flexibility ◽

Intrinsic Excitability ◽

Projection Neurons ◽

Indirect Pathway ◽

Reversal Task ◽

Female Mice ◽

Sham Surgery ◽

Hormonal Modulation ◽

Choice Policy ◽

Dorsomedial Striatum

Decision-making circuits are modulated across life stages (e.g. juvenile, adolescent, or adult)—as well as on the shorter timescale of reproductive cycles in females—to meet changing environmental and physiological demands. Ovarian hormonal modulation of relevant neural circuits is a potential mechanism by which behavioral flexibility is regulated in females. Here we examined the influence of prepubertal ovariectomy (pOVX) versus sham surgery on performance in an odor-based multiple choice reversal task. We observed that pOVX females made different types of errors during reversal learning compared to sham surgery controls. Using reinforcement learning models fit to trial-by-trial behavior, we found that pOVX females exhibited lower inverse temperature parameter (β) compared to sham females. These findings suggest that OVX females solve the reversal task using a more exploratory choice policy, whereas sham females use a more exploitative policy prioritizing estimated high value options. To seek a neural correlate of this behavioral difference, we performed whole-cell patch clamp recordings within the dorsomedial striatum (DMS), a region implicated in regulating action selection and explore/exploit choice policy. We found that the intrinsic excitability of dopamine receptor type 2 (D2R) expressing indirect pathway spiny projection neurons (iSPNs) was significantly higher in pOVX females compared to both unmanipulated and sham surgery females. Finally, to test whether mimicking this increase in iSPN excitability could recapitulate the pattern of reversal task behavior observed in pOVX females, we chemogenetically activated DMS D2R(+) neurons within intact female mice. We found that chemogenetic activation increased exploratory choice during reversal, similar to the pattern we observed in pOVX females. Together, these data suggest that pubertal status may influence explore/exploit balance in females via the modulation of iSPN intrinsic excitability within the DMS.

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Striatal direct and indirect pathway neurons differentially control the encoding and updating of goal-directed learning

10.1101/2020.02.18.955385 ◽

2020 ◽

Author(s):

James Peak ◽

Billy Chieng ◽

Genevra Hart ◽

Bernard W. Balleine

Keyword(s):

Response Bias ◽

Projection Neurons ◽

Indirect Pathway ◽

Response Flexibility ◽

Directed Action ◽

Elevated Expression ◽

Directed Learning ◽

Series Of Experiments ◽

Dorsomedial Striatum

SummaryThe posterior dorsomedial striatum (pDMS) is necessary for goal-directed action, however the role of the direct (dSPN) and indirect (iSPN) spiny projection neurons in the pDMS in such action remains unclear. In this series of experiments, we examined the role of pDMS SPNs in goal-directed action and found that, whereas dSPNs were critical for goal-directed learning and for energizing the learned response, iSPNs were involved in updating that learning to support response flexibility. Instrumental training elevated expression of the plasticity marker Zif268 in dSPNs only, and chemogenetic suppression of dSPN activity during training prevented goal-directed learning. Unilateral optogenetic inhibition of dSPNs induced an ipsilateral response bias in goal-directed action performance. In contrast, although initial goal-directed learning was unaffected by iSPN manipulations, optogenetic inhibition of iSPNs, but not dSPNs, impaired the updating of this learning and attenuated response flexibility after changes in the action-outcome contingency.

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Complete representation of action space and value in all striatal pathways

10.1101/2020.03.29.983825 ◽

2020 ◽

Cited By ~ 2

Author(s):

Moritz Weglage ◽

Emil Wärnberg ◽

Iakovos Lazaridis ◽

Ourania Tzortzi ◽

Konstantinos Meletis

Keyword(s):

Large Scale ◽

Dorsal Striatum ◽

Action Space ◽

Projection Neurons ◽

Indirect Pathway ◽

Complete Representation ◽

Decision Variables ◽

The Matrix ◽

Action Value ◽

Dorsomedial Striatum

ABSTRACTThe dorsal striatum plays a central role in motor and decision programs, such as the selection and execution of particular actions and the evaluation of their outcomes. A standard model has emerged where distinct output pathways encode separate motor-action signals, including selection-evaluation division in the matrix versus patch compartments. We used large-scale cell-type specific calcium imaging during motor and decision behaviors to determine and contrast the activity of individual striatal projection neurons (SPNs) belonging to one of the three major output pathways in the dorsomedial striatum – patch Oprm1+ SPNs versus the D1+ direct and A2A+ indirect pathway. We found that Oprm1+ SPNs were tuned to a number of different behavioral categories, such as to different movements, or to discrete actions and decisions in a two-choice task, and these complex representations were found to the same extent in all three striatal output pathways. The sharp tuning of individual SPNs was highly stereotyped over time while performing a specific task, but the tuning profile remapped between different behavioral contexts. In addition to action representations, SPNs showed pathway-independent representation of decision-variables such as the trial strategy and the action value. We propose that all three major output pathways in the dorsomedial striatum share a similarly complete representation of the entire action space, including task- and phase-specific signals of action value and choice.

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