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

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.

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

eLife ◽  
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.

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

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.

scholarly journals Characterization of striatal dopamine projections across striatal subregions in behavioral flexibility

2021 ◽  
Author(s):  
R.K. van der Merwe ◽  
J.A. Nadel ◽  
D. Copes-Finke ◽  
S. Pawelko ◽  
J.S. Scott ◽  
...  
Keyword(s):  
Dopamine Release ◽  
Dynamic Environment ◽  
Behavioral Flexibility ◽  
Reversal Task ◽  
Causative Mechanism ◽  
Extended Training ◽  
Contingency Reversal ◽  
Striatal Function ◽  
Dorsomedial Striatum

AbstractBehavioral flexibility is key to survival in a dynamic environment. While flexible, goal-directed behaviors are initially dependent on dorsomedial striatum, they become dependent on lateral striatum with extended training as behaviors become inflexible. Similarly, dopamine release shifts from ventromedial to lateral striatum across learning, and impairment of lateral dopamine release disrupts habitual, inflexible responding. This raises the possibility that lateral dopamine release is a causative mechanism in establishing inflexible behaviors late in training, though this has not been directly tested. Here, we utilized optogenetics to activate dopamine terminals in dorsal medial (DMS), dorsal lateral (DLS), and ventral (NAc) striatum in DATcre mice to determine how specific dopamine subpopulations impact behavioral flexibility. Mice performed a reversal task in which they self-stimulated DMS, DLS, or NAc dopamine terminals by pressing one of two levers before action-outcome lever contingencies were reversed. Consistent with presumed ventromedial/lateral striatal function, we found that mice self-stimulating ventromedial dopamine terminals rapidly reversed lever preference following contingency reversal, while mice self-stimulating dopamine terminals in DLS showed impaired reversal learning. These impairments were characterized by more regressive errors and reliance on lose-stay strategies following reversal, suggesting reward insensitivity and overreliance on previously learned actions. This study supports a model of striatal function in which dorsomedial dopamine facilitates goal-directed responding, and dorsolateral dopamine release is a key mechanism in supporting the transition toward inflexible behaviors.

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

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.

scholarly journals Complete representation of action space and value in all striatal pathways

2020 ◽  
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.

Bursting in Substantia Nigra Pars Reticulata Neurons In Vitro: Possible Relevance for Parkinson Disease

2007 ◽  
Vol 98 (4) ◽  
pp. 2311-2323 ◽  
Author(s):  
Osvaldo Ibáñez-Sandoval ◽  
Luis Carrillo-Reid ◽  
Elvira Galarraga ◽  
Dagoberto Tapia ◽  
Ernesto Mendoza ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Parkinson Disease ◽  
Temporal Structure ◽  
Projection Neurons ◽  
Rate Model ◽  
Indirect Pathway ◽  
Bath Application ◽  
Pattern Generators ◽  
Oscillatory Model

Projection neurons of the substantia nigra reticulata (SNr) convey basal ganglia (BG) processing to thalamocortical and brain stem circuits responsible for movement. Two models try to explain pathological BG performance during Parkinson disease (PD): the rate model, which posits an overexcitation of SNr neurons due to hyperactivity in the indirect pathway and hypoactivity of the direct pathway, and the oscillatory model, which explains PD as the product of pathological pattern generators disclosed by dopamine reduction. These models are, apparently, incompatible. We tested the predictions of the rate model by increasing the excitatory drive and reducing the inhibition on SNr neurons in vitro. This was done pharmacologically with bath application of glutamate agonist N-methyl-d-aspartate and GABAA receptor blockers, respectively. Both maneuvers induced bursting behavior in SNr neurons. Therefore synaptic changes forecasted by the rate model induce the electrical behavior predicted by the oscillatory model. In addition, we found evidence that CaV3.2 Ca2+ channels are a critical step in generating the bursting firing pattern in SNr neurons. Other ion channels involved are: hyperpolarization-activated cation channels, high-voltage-activated Ca2+ channels, and Ca2+-activated K+ channels. However, although these channels shape the temporal structure of bursting, only CaV3.2 Ca2+ channels are indispensable for the initiation of the bursting pattern.

scholarly journals Control of Basal Ganglia Output by Direct and Indirect Pathway Projection Neurons

2013 ◽  
Vol 33 (47) ◽  
pp. 18531-18539 ◽  
Author(s):  
B. S. Freeze ◽  
A. V. Kravitz ◽  
N. Hammack ◽  
J. D. Berke ◽  
A. C. Kreitzer
Keyword(s):  
Basal Ganglia ◽  
Projection Neurons ◽  
Indirect Pathway

Visualization of zebrafish striatum direct and indirect pathway projection neurons

2011 ◽  
Vol 71 ◽  
pp. e372
Author(s):  
Ryo Aoki ◽  
Tazu Aoki ◽  
Masakazu Agetsuma ◽  
Toshiyuki Shiraki ◽  
Takashi Tsuboi ◽  
...  
Keyword(s):  
Projection Neurons ◽  
Indirect Pathway

scholarly journals Stroke Induces a BDNF-Dependent Improvement in Cognitive Flexibility in Aged Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Josh Houlton ◽  
Lisa Y. Y. Zhou ◽  
Deanna Barwick ◽  
Emma K. Gowing ◽  
Andrew N. Clarkson
Keyword(s):  
Animal Model ◽  
Cognitive Flexibility ◽  
Cognitive Deficits ◽  
Cox Regression ◽  
Reversal Task ◽  
Critical Window ◽  
Aged Mice ◽  
Sham Surgery ◽  
Age Related ◽  
Old Mice

Stroke remains a leading cause of disability worldwide. Recently, we have established an animal model of stroke that results in delayed impairment in spatial memory, allowing us to better investigate cognitive deficits. Young and aged brains show different recovery profiles after stroke; therefore, we assessed aged-related differences in poststroke cognition. As neurotrophic support diminishes with age, we also investigated the involvement of brain-derived neurotrophic factor (BDNF) in these differences. Young (3-6 months old) and aged (16-21 months old) mice were trained in operant touchscreen chambers to complete a visual pairwise discrimination (VD) task. Stroke or sham surgery was induced using the photothrombotic model to induce a bilateral prefrontal cortex stroke. Five days poststroke, an additional cohort of aged stroke animals were treated with intracerebral hydrogels loaded with the BDNF decoy, TrkB-Fc. Following treatment, animals underwent the reversal and rereversal task to identify stroke-induced cognitive deficits at days 17 and 37 poststroke, respectively. Assessment of sham animals using Cox regression and log-rank analyses showed aged mice exhibit an increased impairment on VD reversal and rereversal learning compared to young controls. Stroke to young mice revealed no impairment on either task. In contrast, stroke to aged mice facilitated a significant improvement in reversal learning, which was dampened in the presence of the BDNF decoy, TrkB-Fc. In addition, aged stroke control animals required significantly less consecutive days and correction trials to master the reversal task, relative to aged shams, an effect dampened by TrkB-Fc. Our findings support age-related differences in recovery of cognitive function after stroke. Interestingly, aged stroke animals outperformed their sham counterparts, suggesting reopening of a critical window for recovery that is being mediated by BDNF.

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