@article{willett_cao_dorris_johnson_ginnari_meitzen_2019, title={Electrophysiological Properties of Medium Spiny Neuron Subtypes in the Caudate-Putamen of Prepubertal Male and Female Drd1a-tdTomato Line 6 BAC Transgenic Mice}, volume={6}, ISSN={["2373-2822"]}, DOI={10.1523/ENEURO.0016-19.2019}, abstractNote={AbstractThe caudate-putamen is a striatal brain region essential for sensorimotor behaviors, habit learning, and other cognitive and premotor functions. The output and predominant neuron of the caudate-putamen is the medium spiny neuron (MSN). MSNs present discrete cellular subtypes that show differences in neurochemistry, dopamine receptor expression, efferent targets, gene expression, functional roles, and most importantly for this study, electrophysiological properties. MSN subtypes include the striatonigral and the striatopallidal groups. Most studies identify the striatopallidal MSN subtype as being more excitable than the striatonigral MSN subtype. However, there is some divergence between studies regarding the exact differences in electrophysiological properties. Furthermore, MSN subtype electrophysiological properties have not been reported disaggregated by biological sex. We addressed these questions using prepubertal male and female Drd1a-tdTomato line 6 BAC transgenic mice, an important transgenic line that has not yet received extensive electrophysiological analysis. We made acute caudate-putamen brain slices and assessed a robust battery of 16 relevant electrophysiological properties using whole-cell patch-clamp recording, including intrinsic membrane, action potential, and miniature EPSC (mEPSC) properties. We found that: (1) MSN subtypes exhibited multiple differential electrophysiological properties in both sexes, including rheobase, action potential threshold and width, input resistance in both the linear and rectified ranges, and mEPSC amplitude; (2) select electrophysiological properties showed interactions between MSN subtype and sex. These findings provide a comprehensive evaluation of mouse caudate-putamen MSN subtype electrophysiological properties across females and males, both confirming and extending previous studies.}, number={2}, journal={ENEURO}, author={Willett, Jaime A. and Cao, Jinyan and Dorris, David M. and Johnson, Ashlyn G. and Ginnari, Laura A. and Meitzen, John}, year={2019} }
 @article{willett_cao_johnson_patel_dorris_meitzen_2020, title={The estrous cycle modulates rat caudate-putamen medium spiny neuron physiology}, volume={52}, ISSN={["1460-9568"]}, DOI={10.1111/ejn.14506}, abstractNote={AbstractThe neuroendocrine environment in which the brain operates is both dynamic and differs by sex. How differences in neuroendocrine state affect neuron properties has been significantly neglected in neuroscience research. Behavioral data across humans and rodents indicate that natural cyclical changes in steroid sex hormone production affect sensorimotor and cognitive behaviors in both normal and pathological contexts. These behaviors are critically mediated by the caudate–putamen. In the caudate–putamen, medium spiny neurons (MSNs) are the predominant and primary output neurons. MSNs express membrane‐associated estrogen receptors and demonstrate estrogen sensitivity. However, how the cyclical hormone changes across the estrous cycle may modulate caudate–putamen MSN electrophysiological properties remains unknown. Here, we performed whole‐cell patch‐clamp recordings on male, diestrus female, proestrus female, and estrus female caudate–putamen MSNs. Action potential, passive membrane, and miniature excitatory post‐synaptic current properties were assessed. Numerous MSN electrical properties robustly differed by cycle state, including resting membrane potential, rheobase, action potential threshold, maximum evoked action potential firing rate, and inward rectification. Strikingly, when considered independent of estrous cycle phase, all but one of these properties do not significantly differ from male MSNs. These data indicate that female caudate–putamen MSNs are sensitive to the estrous cycle, and more broadly, the importance of considering neuroendocrine state in studies of neuron physiology.}, number={1}, journal={EUROPEAN JOURNAL OF NEUROSCIENCE}, author={Willett, Jaime A. and Cao, Jinyan and Johnson, Ashlyn and Patel, Opal H. and Dorris, David M. and Meitzen, John}, year={2020}, month={Jul}, pages={2737–2755} }
 @misc{cao_willett_dorris_meitzen_2018, title={Sex Differences in Medium Spiny neuron excitability and Glutamatergic Synaptic input: Heterogeneity Across Striatal Regions and evidence for Estradiol-Dependent Sexual Differentiation}, volume={9}, ISSN={["1664-2392"]}, DOI={10.3389/fendo.2018.00173}, abstractNote={Steroid sex hormones and biological sex influence how the brain regulates motivated behavior, reward, and sensorimotor function in both normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the caudate–putamen, nucleus accumbens core (AcbC), and shell. These brain regions are of particular interest to neuroendocrinologists given that they express membrane-associated but not nuclear estrogen receptors, and also the well-established role of the sex steroid hormone 17β-estradiol (estradiol) in modulating striatal dopamine systems. Indeed, output neurons of the striatum, the medium spiny neurons (MSNs), exhibit estradiol sensitivity and sex differences in electrophysiological properties. Here, we review sex differences in rat MSN glutamatergic synaptic input and intrinsic excitability across striatal regions, including evidence for estradiol-mediated sexual differentiation in the nucleus AcbC. In prepubertal animals, female MSNs in the caudate–putamen exhibit a greater intrinsic excitability relative to male MSNs, but no sex differences are detected in excitatory synaptic input. Alternatively, female MSNs in the nucleus AcbC exhibit increased excitatory synaptic input relative to male MSNs, but no sex differences in intrinsic excitability were detected. Increased excitatory synaptic input onto female MSNs in the nucleus AcbC is abolished after masculinizing estradiol or testosterone exposure during the neonatal critical period. No sex differences are detected in MSNs in prepubertal nucleus accumbens shell. Thus, despite possessing the same neuron type, striatal regions exhibit heterogeneity in sex differences in MSN electrophysiological properties, which likely contribute to the sex differences observed in striatal function.}, journal={FRONTIERS IN ENDOCRINOLOGY}, author={Cao, Jinyan and Willett, Jaime A. and Dorris, David M. and Meitzen, John}, year={2018}, month={Apr} }
 @article{willett_will_hauser_dorris_cao_meitzen_2016, title={No Evidence for Sex Differences in the Electrophysiological Properties and Excitatory Synaptic Input onto Nucleus Accumbens Shell Medium Spiny Neurons}, volume={3}, ISSN={["2373-2822"]}, DOI={10.1523/eneuro.0147-15.2016}, abstractNote={Visual Overview Sex differences exist in how the brain regulates motivated behavior and reward, both in normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the dorsal striatum and nucleus accumbens core and shell. Sex differences exist in how the brain regulates motivated behavior and reward, both in normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the dorsal striatum and nucleus accumbens core and shell. These investigations yield accumulating evidence of sexually different electrophysiological properties, excitatory synaptic input, and sensitivity to neuromodulator/hormone action in select striatal regions both before and after puberty. It is unknown whether the electrical properties of neurons in the nucleus accumbens shell differ by sex, and whether sex differences in excitatory synaptic input are present before puberty. To test the hypothesis that these properties differ by sex, we performed whole-cell patch-clamp recordings on male and female medium spiny neurons (MSNs) in acute brain slices obtained from prepubertal rat nucleus accumbens shell. We analyzed passive and active electrophysiological properties, and miniature EPSCs (mEPSCs). No sex differences were detected; this includes those properties, such as intrinsic excitability, action potential afterhyperpolarization, threshold, and mEPSC frequency, that have been found to differ by sex in other striatal regions and/or developmental periods. These findings indicate that, unlike other striatal brain regions, the electrophysiological properties of nucleus accumbens shell MSNs do not differ by sex. Overall, it appears that sex differences in striatal function, including motivated behavior and reward, are likely mediated by other factors and striatal regions.}, number={1}, journal={ENEURO}, author={Willett, Jaime A. and Will, Tyler and Hauser, Caitlin A. and Dorris, David M. and Cao, Jinyan and Meitzen, John}, year={2016} }
 @article{dorris_cao_willett_hauser_meitzen_2015, title={Intrinsic excitability varies by sex in prepubertal striatal medium spiny neurons}, volume={113}, ISSN={["1522-1598"]}, DOI={10.1152/jn.00687.2014}, abstractNote={ Sex differences in neuron electrophysiological properties were traditionally associated with brain regions directly involved in reproduction in adult, postpubertal animals. There is growing acknowledgement that sex differences can exist in other developmental periods and brain regions as well. This includes the dorsal striatum (caudate/putamen), which shows robust sex differences in gene expression, neuromodulator action (including dopamine and 17β-estradiol), and relevant sensorimotor behaviors and pathologies such as the responsiveness to drugs of abuse. Here we examine whether these sex differences extend to striatal neuron electrophysiology. We test the hypothesis that passive and active medium spiny neuron (MSN) electrophysiological properties in prepubertal rat dorsal striatum differ by sex. We made whole cell recordings from male and females MSNs from acute brain slices. The slope of the evoked firing rate to current injection curve was increased in MSNs recorded from females compared with males. The initial action potential firing rate was increased in MSNs recorded from females compared with males. Action potential after-hyperpolarization peak was decreased, and threshold was hyperpolarized in MSNs recorded from females compared with males. No sex differences in passive electrophysiological properties or miniature excitatory synaptic currents were detected. These findings indicate that MSN excitability is increased in prepubertal females compared with males, providing a new mechanism that potentially contributes to generating sex differences in striatal-mediated processes. Broadly, these findings demonstrate that sex differences in neuron electrophysiological properties can exist prepuberty in brain regions not directly related to reproduction. }, number={3}, journal={JOURNAL OF NEUROPHYSIOLOGY}, author={Dorris, David M. and Cao, Jinyan and Willett, Jaime A. and Hauser, Caitlin A. and Meitzen, John}, year={2015}, month={Feb}, pages={720–729} }