Activation, but not inhibition, of the indirect pathway disrupts choice rejection in a freely moving, multiple-choice foraging task

The dorsomedial striatum (DMS) plays a key role in action selection, but less is known about how direct and indirect pathway spiny projection neurons (dSPNs and iSPNs, respectively) contribute to choice rejection in freely moving animals. Here, we use pathway-specific chemogenetic manipulation during a serial choice foraging task to test the role of dSPNs and iSPNs in learned choice rejection. We find that chemogenetic activation, but not inhibition, of iSPNs disrupts rejection of nonrewarded choices, contrary to predictions of a simple “select/suppress” heuristic. Our findings suggest that iSPNs’ role in stopping and freezing does not extend in a simple fashion to choice rejection in an ethological, freely moving context. These data may provide insights critical for the successful design of interventions for addiction or other conditions in which it is desirable to strengthen choice rejection.

Kristen Delevich,  Benjamin Hoshal, Lexi Z. Zhou, Yuting Zhang, Satya Vedula, Wan Chen Lin, Juliana Chase, Anne G.E. Collins, Linda Wilbrecht, Activation, but not inhibition, of the indirect pathway disrupts choice rejection in a freely moving, multiple-choice foraging task, 40(4) Cell Reports 111129 (July 26, 2022). DOI: https://doi.org/10.1016/j.celrep.2022.111129

Activation, but not inhibition, of the indirect pathway disrupts choice rejection in a freely moving, multiple-choice foraging task2022-07-29T03:19:24+00:00

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

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.

Kristen Delevich, Christopher D. Hall, Linda Wilbrecht, Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice, BioRxiv, https://www.biorxiv.org/content/10.1101/2021.06.01.446609v2, doi: https://doi.org/10.1101/2021.06.01.446609

Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice2021-06-17T13:40:25+00:00

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

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.

Kristen Delevich, Christopher D. Hall, Linda Wilbrecht, Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice, BioRxiv, June 1, 2021, https://www.biorxiv.org/content/10.1101/2021.06.01.446609v1
doi: https://doi.org/10.1101/2021.06.01.446609

Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice2022-07-29T03:12:19+00:00

Coming of age in the frontal cortex: The role of puberty in cortical maturation

Across species, adolescence is a period of growing independence that is associated with the maturation of cognitive, social, and affective processing. Reorganization of neural circuits within the frontal cortex is believed to contribute to the emergence of adolescent changes in cognition and behavior. While puberty coincides with adolescence, relatively little is known about which aspects of frontal cortex maturation are driven by pubertal development and gonadal hormones. In this review, we highlight existing work that suggests puberty plays a role in the maturation of specific cell types in the medial prefrontal cortex (mPFC) of rodents, and highlight possible routes by which gonadal hormones influence frontal cortical circuit development.

Kristen Delevich, Madeline Klinger, Nana J.Okada, Linda Wilbrecht, Coming of age in the frontal cortex: The role of puberty in cortical maturation, May 10, 2021, https://www.sciencedirect.com/science/article/pii/S108495212100094X
Coming of age in the frontal cortex: The role of puberty in cortical maturation2021-06-02T16:26:26+00:00

A role for adaptive developmental plasticity in learning and decision making

From both a medical and educational perspective, there is enormous value to understanding the environmental factors that sculpt learning and decision making. These questions are often approached from proximate levels of analysis, but may be further informed by the adaptive developmental plasticity framework used in evolutionary biology. The basic adaptive developmental plasticity framework posits that biological sensitive periods evolved to use information from the environment to sculpt emerging phenotypes. Here, we lay out how we can apply this framework to learning and decision making in the mammalian brain and propose a working model in which dopamine neurons and their activity may serve to inform downstream circuits about environmental statistics. More widespread use of this evolutionary framework and its associated models can help inform and guide basic research and intervention science.

Wan Chen Lin, Kristen Delevich, Linda Wilbrecht, A role for adaptive developmental plasticity in learning and decision making, 36 Current Opinion in Behavioral Sciences pp 48–54 (2020), https://doi.org/10.1016/j.cobeha.2020.07.010, http://www.sciencedirect.com/science/article/pii/S2352154620301121

A role for adaptive developmental plasticity in learning and decision making2021-06-02T16:28:40+00:00

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

The 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.

Kristen Delevich, Benjamin Hoshal, Anne GE Collins, Linda Wilbrecht, Choice suppression is achieved through opponent but not independent function of the striatal indirect pathway in mice, BioRxiv, https://www.biorxiv.org/content/10.1101/675850v3
doi: https://doi.org/10.1101/675850

 

Choice suppression is achieved through opponent but not independent function of the striatal indirect pathway in mice2022-06-18T20:52:41+00:00

Sex and Pubertal Status Influence Dendritic Spine Density on Frontal Corticostriatal Projection Neurons in Mice

In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends into adolescence. This maturation is believed to support higher cognition but may also confer psychiatric vulnerability during adolescence. Currently, little is known about how specific cell types in the frontal cortex mature or whether puberty plays a role in the maturation of some cell types but not others. Here, we used mice to characterize the spatial topography and adolescent development of cross-corticostriatal (cSTR) neurons that project through the corpus collosum to the dorsomedial striatum. We found that apical spine density on cSTR neurons in the medial prefrontal cortex decreased significantly between late juvenile (P29) and young adult time points (P60), with females exhibiting higher spine density than males at both ages. Adult males castrated prior to puberty onset had higher spine density compared to sham controls. Adult females ovariectomized before puberty onset showed greater variance in spine density measures on cSTR cells compared to controls, but their mean spine density did not significantly differ from sham controls. Our findings reveal that these cSTR neurons, a subtype of the broader class of intratelencephalic-type neurons, exhibit significant sex differences and suggest that spine pruning on cSTR neurons is regulated by puberty in male mice.

Kristen Delevich, Nana J Okada, Ameet Rahane, Zicheng Zhang, Christopher D Hall, Linda Wilbrecht, Sex and Pubertal Status Influence Dendritic Spine Density on Frontal Corticostriatal Projection Neurons in Mice, Cerebral Cortex, , bhz325, https://doi.org/10.1093/cercor/bhz325 (preprint available at https://www.biorxiv.org/content/biorxiv/early/2019/09/30/787408.full.pdf)

Sex and Pubertal Status Influence Dendritic Spine Density on Frontal Corticostriatal Projection Neurons in Mice2020-02-13T03:35:21+00:00

Variation in early life maternal care predicts later long range frontal cortex synapse development in mice

Empirical and theoretical work suggests that early postnatal experience may inform later developing synaptic connectivity to adapt the brain to its environment. We hypothesized that early maternal experience may program the development of synaptic density on long range frontal cortex projections. To test this idea, we used maternal separation (MS) to generate environmental variability and examined how MS affected 1) maternal care and 2) synapse density on virally-labeled long range axons of offspring reared in MS or control conditions. We found that MS and variation in maternal care predicted bouton density on dorsal frontal cortex axons that terminated in the basolateral amygdala (BLA) and dorsomedial striatum (DMS) with more, fragmented care associated with higher density. The effects of maternal care on these distinct axonal projections of the frontal cortex were manifest at different ages. Maternal care measures were correlated with frontal cortex → BLA bouton density at mid-adolescence postnatal (P) day 35 and frontal cortex → DMS bouton density in adulthood (P85). Meanwhile, we found no evidence that MS or maternal care affected bouton density on ascending orbitofrontal cortex (OFC) or BLA axons that terminated in the dorsal frontal cortices. Our data show that variation in early experience can alter development in a circuit-specific and age-dependent manner that may be relevant to early life adversity.

A. Wren Thomas, Kristen Delevich, Irene Chang, Linda Wilbrecht, Variation in early life maternal care predicts later long range frontal cortex synapse development in mice, Developmental Cognitive Neuroscience (2009)
https://doi.org/10.1016/j.dcn.2019.100737, http://www.sciencedirect.com/science/article/pii/S187892931930324X

Variation in early life maternal care predicts later long range frontal cortex synapse development in mice2019-11-20T23:02:33+00:00

Kristen Delevich Awarded Tourette Association of America Funding

The Tourette Association of America has awarded its Young Investigator Award to Kristen Delevich for her research project, Studying the Influence of Hormones on the Brain. This work seeks to understand the influence of puberty on brain circuits involved in behavioral control, in an effort to elucidate why Tourette symptoms typically change during adolescence. Congratulations, Dr. Delevich!

Kristen Delevich Awarded Tourette Association of America Funding2019-10-17T22:14:02+00:00

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