@article{plessis_basu_rumbell_lucas_2022, title={Sex-Specific Neural Networks of Cued Threat Conditioning: A Pilot Study}, volume={16}, ISSN={["1662-5137"]}, DOI={10.3389/fnsys.2022.832484}, abstractNote={Cued threat conditioning is the most common preclinical model for emotional memory, which is dysregulated in anxiety disorders and post-traumatic stress disorder. Though women are twice as likely as men to develop these disorders, current knowledge of threat conditioning networks was established by studies that excluded female subjects. For unbiased investigation of sex differences in these networks, we quantified the neural activity marker c-fos across 112 brain regions in adult male and female mice after cued threat conditioning compared to naïve controls. We found that trained females engaged prelimbic cortex, lateral amygdala, cortical amygdala, dorsal peduncular cortex, and subparafasicular nucleus more than, and subparaventricular zone less than, trained males. To explore how these sex differences in regional activity impact the global network, we generated interregional cross-correlations of c-fos expression to identify regions that were co-active during conditioning and performed hub analyses to identify regional control centers within each neural network. These exploratory graph theory-derived analyses revealed sex differences in the functional coordination of the threat conditioning network as well as distinct hub regions between trained males and females. Hub identification across multiple networks constructed by sequentially pruning the least reliable connections revealed globus pallidus and ventral lateral septum as the most robust hubs for trained males and females, respectively. While low sample size and lack of non-associative controls are major limitations, these findings provide preliminary evidence of sex differences in the individual circuit components and broader global networks of threat conditioning that may confer female vulnerability to fear-based psychiatric disease.}, journal={FRONTIERS IN SYSTEMS NEUROSCIENCE}, author={Plessis, Kamryn C. and Basu, Sreetama and Rumbell, Timothy H. and Lucas, Elizabeth K.}, year={2022}, month={May} }
 @article{lucas_wu_roman-ortiz_clem_2019, title={Prazosin during fear conditioning facilitates subsequent extinction in male C57Bl/6N mice}, volume={236}, ISSN={["1432-2072"]}, DOI={10.1007/s00213-018-5001-x}, abstractNote={Recovery from a traumatic experience requires extinction of cue-based fear responses, a process that is impaired in post-traumatic stress disorder. While studies suggest a link between fear behavioral flexibility and noradrenaline signaling, the role of specific receptors and brain regions in these effects is unclear. Here, we examine the role of prazosin, an α1-adrenergic receptor (α1-AR) antagonist, in auditory fear conditioning and extinction. C57Bl/6N mice were subjected to auditory fear conditioning and extinction in combination with systemic (0.1–2 mg/kg) or local microinjections (3 or 6 mM) of the α1-AR antagonist prazosin into the prelimbic division of medial prefrontal cortex or basolateral amygdala. Conditioned fear and anxiety-like behaviors were compared with vehicle-injected control animals. Mice that received systemic prazosin prior to fear conditioning exhibited similar initial levels of cue-elicited freezing compared to vehicle controls on the following day. However, at all doses tested, fear that was acquired during prazosin treatment was more readily extinguished, whereas anxiety-like behavior on the day of extinction was unaffected. A similar pattern of results was observed when prazosin was microinjected into the basolateral amygdala but not the prelimbic cortex. In contrast to pre-conditioning injections, prazosin administration prior to extinction had no effect on freezing. Our results indicate that α1-AR activity during aversive conditioning is dispensable for memory acquisition but renders conditioned fear more impervious to extinction. This suggests that behavioral flexibility is constrained by noradrenaline at the time of initial learning via activation of a specific AR isoform.}, number={1}, journal={PSYCHOPHARMACOLOGY}, author={Lucas, Elizabeth K. and Wu, Wan-Chen and Roman-Ortiz, Ciorana and Clem, Roger L.}, year={2019}, month={Jan}, pages={273–279} }
 @article{lucas_clem_2018, title={GABAergic interneurons: the orchestra or the conductor in fear learning and memory?}, volume={141}, DOI={10.1016/j.brainresbull.2017.11.016}, abstractNote={Fear conditioning is a form of associative learning that is fundamental to survival and involves potentiation of activity in excitatory projection neurons (PNs). Current models stipulate that the mechanisms underlying this process involve plasticity of PN synapses, which exhibit strengthening in response to fear conditioning. However, excitatory PNs are extensively modulated by a diverse array of GABAergic interneurons whose contributions to acquisition, storage, and expression of fear memory remain poorly understood. Here we review emerging evidence that genetically-defined interneurons play important subtype-specific roles in processing of fear-related stimuli and that these dynamics shape PN firing through both inhibition and disinhibition. Furthermore, interneurons exhibit structural, molecular, and electrophysiological evidence of fear learning-induced synaptic plasticity. These studies warrant discarding the notion of interneurons as passive bystanders in long-term memory.}, journal={Brain Research Bulletin}, author={Lucas, E.K. and Clem, R.L.}, year={2018}, month={Jul}, pages={13–19} }
 @article{lucas_jegarl_morishita_clem_2016, title={Multimodal and Site-Specific Plasticity of Amygdala Parvalbumin Interneurons after Fear Learning}, volume={91}, ISSN={0896-6273}, url={http://dx.doi.org/10.1016/j.neuron.2016.06.032}, DOI={10.1016/j.neuron.2016.06.032}, abstractNote={Stimulus processing in fear conditioning is constrained by parvalbumin interneurons (PV-INs) through inhibition of principal excitatory neurons. However, the contributions of PV-IN microcircuits to input gating and long-term plasticity in the fear system remain unknown. Here we interrogate synaptic connections between afferent pathways, PV-INs, and principal excitatory neurons in the basolateral amygdala. We find that subnuclei of this region are populated two functionally distinct PV-IN networks. PV-INs in the lateral (LA), but not the basal (BA), amygdala possess complex dendritic arborizations, receive potent excitatory drive, and mediate feedforward inhibition onto principal neurons. After fear conditioning, PV-INs exhibit nucleus- and target-selective plasticity, resulting in persistent reduction of their excitatory input and inhibitory output in LA but not BA. These data reveal previously overlooked specializations of amygdala PV-INs and indicate specific circuit mechanisms for inhibitory plasticity during the encoding of associative fear memories.}, number={3}, journal={Neuron}, publisher={Elsevier BV}, author={Lucas, Elizabeth K. and Jegarl, Anita M. and Morishita, Hirofumi and Clem, Roger L.}, year={2016}, month={Aug}, pages={629–643} }
 @article{lucas_reid_mcmeekin_dougherty_cowell_2015, title={Cerebellar transcriptional alterations with Purkinje cell dysfunction and loss in mice lacking PGC-1α}, volume={441}, DOI={10.3389/fncel.2014.00441}, abstractNote={Alterations in the expression and activity of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (ppargc1a or PGC-1α) have been reported in multiple movement disorders, yet it is unclear how a lack of PGC-1α impacts transcription and function of the cerebellum, a region with high PGC-1α expression. We show here that mice lacking PGC-1α exhibit ataxia in addition to the previously described deficits in motor coordination. Using q-RT-PCR in cerebellar homogenates from PGC-1α−/− mice, we measured expression of 37 microarray-identified transcripts upregulated by PGC-1α in SH-SY5Y neuroblastoma cells with neuroanatomical overlap with PGC-1α or parvalbumin (PV), a calcium buffer highly expressed by Purkinje cells. We found significant reductions in transcripts with synaptic (complexin1, Cplx1; Pacsin2), structural (neurofilament heavy chain, Nefh), and metabolic (isocitrate dehydrogenase 3a, Idh3a; neutral cholesterol ester hydrolase 1, Nceh1; pyruvate dehydrogenase alpha 1, Pdha1; phytanoyl-CoA hydroxylase, Phyh; ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1, Uqcrfs1) functions. Using conditional deletion of PGC-1α in PV-positive neurons, we determined that 50% of PGC-1α expression and a reduction in a subset of these transcripts could be explained by its concentration in PV-positive neuronal populations in the cerbellum. To determine whether there were functional consequences associated with these changes, we conducted stereological counts and spike rate analysis in Purkinje cells, a cell type rich in PV, from PGC-1α−/− mice. We observed a significant loss of Purkinje cells by 6 weeks of age, and the remaining Purkinje cells exhibited a 50% reduction in spike rate. Together, these data highlight the complexity of PGC-1α's actions in the central nervous system and suggest that dysfunction in multiple cell types contribute to motor deficits in the context of PGC-1α deficiency.}, number={8}, journal={Frontiers in Cellular Neuroscience, Special Issue, Neurodegeneration: from Genetics to Molecules}, author={Lucas, E.K. and Reid, C.S. and McMeekin, L.J. and Dougherty, S.E. and Cowell, R.M.}, year={2015}, pages={1–13} }
 @article{mcmeekin_lucas_meador-woodruff_mccullumsmith_hendrickson_gamble_cowell_2015, title={Cortical PGC-1α-Dependent Transcripts Are Reduced in Postmortem Tissue From Patients With Schizophrenia}, volume={42}, ISSN={0586-7614 1745-1701}, url={http://dx.doi.org/10.1093/schbul/sbv184}, DOI={10.1093/schbul/sbv184}, abstractNote={The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) has been linked to multiple neurological and psychiatric disorders including schizophrenia, but its involvement in the pathophysiology of these disorders is unclear. Experiments in mice have revealed a set of developmentally-regulated cortical PGC-1α-dependent transcripts involved in calcium buffering (parvalbumin, PV), synchronous neurotransmitter release (synaptotagmin 2, Syt2; complexin 1, Cplx1) and axonal integrity (neurofilamaent heavy chain, Nefh). We measured the mRNA expression of PGC-1α and these transcripts in postmortem cortical tissue from control and schizophrenia patients and found a reduction in PGC-1α-dependent transcripts without a change in PGC-1α. While control subjects with high PGC-1α expression exhibited high PV and Nefh expression, schizophrenia subjects with high PGC-1α expression did not, suggesting dissociation between PGC-1α expression and these targets in schizophrenia. Unbiased analyses of the promoter regions for PGC-1α-dependent transcripts revealed enrichment of binding sites for the PGC-1α-interacting transcription factor nuclear respiratory factor 1 (NRF-1). NRF-1 mRNA expression was reduced in schizophrenia, and its transcript levels predicted that of PGC-1α-dependent targets in schizophrenia. Interestingly, the positive correlation between PGC-1α and PV, Syt2, or Cplx1 expression was lost in schizophrenia patients with low NRF-1 expression, suggesting that NRF-1 is a critical predictor of these genes in disease. These data suggest that schizophrenia involves a disruption in PGC-1α and/or NRF-1-associated transcriptional programs in the cortex and that approaches to enhance the activity of PGC-1α or transcriptional regulators like NRF-1 should be considered with the goal of restoring normal gene programs and improving cortical function.}, number={4}, journal={Schizophrenia Bulletin}, publisher={Oxford University Press (OUP)}, author={McMeekin, Laura J. and Lucas, Elizabeth K. and Meador-Woodruff, James H. and McCullumsmith, Robert E. and Hendrickson, Robert C. and Gamble, Karen L. and Cowell, Rita M.}, year={2015}, month={Dec}, pages={1009–1017} }
 @article{bartley_lucas_brady_li_hablitz_cowell_dobrunz_2015, title={Interneuron Transcriptional Dysregulation Causes Frequency-Dependent Alterations in the Balance of Inhibition and Excitation in Hippocampus}, volume={35}, ISSN={0270-6474 1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.1834-15.2015}, DOI={10.1523/jneurosci.1834-15.2015}, abstractNote={Circuit dysfunction in complex brain disorders such as schizophrenia and autism is caused by imbalances between inhibitory and excitatory synaptic transmission (I/E). Short-term plasticity differentially alters responses from excitatory and inhibitory synapses, causing the I/E ratio to change as a function of frequency. However, little is known about I/E ratio dynamics in complex brain disorders. Transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, is a consistent pathophysiological feature of schizophrenia. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator that in hippocampus is highly concentrated in inhibitory interneurons and regulates parvalbumin transcription. Here, we used PGC-1α−/−mice to investigate effects of interneuron transcriptional dysregulation on the dynamics of the I/E ratio at the synaptic and circuit level in hippocampus. We find that loss of PGC-1α increases the I/E ratio onto CA1 pyramidal cells in response to Schaffer collateral stimulation in slices from young adult mice. The underlying mechanism is enhanced basal inhibition, including increased inhibition from parvalbumin interneurons. This decreases the spread of activation in CA1 and dramatically limits pyramidal cell spiking, reducing hippocampal output. The I/E ratio and CA1 output are partially restored by paired-pulse stimulation at short intervals, indicating frequency-dependent effects. However, circuit dysfunction persists, indicated by alterations in kainate-induced gamma oscillations and impaired nest building. Together, these results show that transcriptional dysregulation in hippocampal interneurons causes frequency-dependent alterations in I/E ratio and circuit function, suggesting that PGC-1α deficiency in psychiatric and neurological disorders contributes to disease by causing functionally relevant alterations in I/E balance.}, number={46}, journal={Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Bartley, A. F. and Lucas, E. K. and Brady, L. J. and Li, Q. and Hablitz, J. J. and Cowell, R. M. and Dobrunz, L. E.}, year={2015}, month={Nov}, pages={15276–15290} }
 @article{lucas_jegarl_clem_2014, title={Mice lacking TrkB in parvalbumin-positive cells exhibit sexually dimorphic behavioral phenotypes}, volume={274}, ISSN={0166-4328}, url={http://dx.doi.org/10.1016/j.bbr.2014.08.011}, DOI={10.1016/j.bbr.2014.08.011}, abstractNote={Activity-dependent brain-derived neurotrophic factor (BDNF) signaling through receptor tyrosine kinase B (TrkB) is required for cued fear memory consolidation and extinction. Although BDNF is primarily secreted from glutamatergic neurons, TrkB is expressed by other genetically defined cells whose contributions to the behavioral effects of BDNF remain poorly understood. Parvalbumin (PV)-positive interneurons, which are highly enriched in TrkB, are emerging as key regulators of fear memory expression. We therefore hypothesized that activity-dependent BDNF signaling in PV-interneurons may modulate emotional learning. To test this hypothesis, we utilized the LoxP/Cre system for conditional deletion of TrkB in PV-positive cells to examine the impact of cell-autonomous BDNF signaling on Pavlovian fear conditioning and extinction. However, behavioral abnormalities indicative of vestibular dysfunction precluded the use of homozygous conditional knockouts in tests of higher cognitive functioning. While vestibular dysfunction was apparent in both sexes, female conditional knockouts exhibited an exacerbated phenotype, including extreme motor hyperactivity and circling behavior, compared to their male littermates. Heterozygous conditional knockouts were spared of vestibular dysfunction. While fear memory consolidation was unaffected in heterozygotes of both sexes, males exhibited impaired extinction consolidation compared to their littermate controls. Our findings complement evidence from human and rodent studies suggesting that BDNF signaling promotes consolidation of extinction and point to PV-positive neurons as a discrete population that mediates these effects in a sex-specific manner.}, journal={Behavioural Brain Research}, publisher={Elsevier BV}, author={Lucas, Elizabeth K. and Jegarl, Anita and Clem, Roger L.}, year={2014}, month={Nov}, pages={219–225} }
 @article{dougherty_bartley_lucas_hablitz_dobrunz_cowell_2014, title={Mice lacking the transcriptional coactivator PGC-1α exhibit alterations in inhibitory synaptic transmission in the motor cortex}, volume={271}, ISSN={0306-4522}, url={http://dx.doi.org/10.1016/j.neuroscience.2014.04.023}, DOI={10.1016/j.neuroscience.2014.04.023}, abstractNote={Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator known to regulate gene programs in a cell-specific manner in energy-demanding tissues, and its dysfunction has been implicated in numerous neurological and psychiatric disorders. Previous work from the Cowell laboratory indicates that PGC-1α is concentrated in inhibitory interneurons and is required for the expression of the calcium buffer parvalbumin (PV) in the cortex; however, the impact of PGC-1α deficiency on inhibitory neurotransmission in the motor cortex is not known. Here, we show that mice lacking PGC-1α exhibit increased amplitudes and decreased frequency of spontaneous inhibitory postsynaptic currents in layer V pyramidal neurons. Upon repetitive train stimulation at the gamma frequency, decreased GABA release is observed. Furthermore, PV-positive interneurons in PGC-1α −/− mice display reductions in intrinsic excitability and excitatory input without changes in gross interneuron morphology. Taken together, these data show that PGC-1α is required for normal inhibitory neurotransmission and cortical PV-positive interneuron function. Given the pronounced motor dysfunction in PGC-1α −/− mice and the essential role of PV-positive interneurons in maintenance of cortical excitatory:inhibitory balance, it is possible that deficiencies in PGC-1α expression could contribute to cortical hyperexcitability and motor abnormalities in multiple neurological disorders.}, journal={Neuroscience}, publisher={Elsevier BV}, author={Dougherty, S.E. and Bartley, A.F. and Lucas, E.K. and Hablitz, J.J. and Dobrunz, L.E. and Cowell, R.M.}, year={2014}, month={Jun}, pages={137–148} }
 @article{lucas_dougherty_mcmeekin_reid_dobrunz_west_hablitz_cowell_2014, title={PGC-1  Provides a Transcriptional Framework for Synchronous Neurotransmitter Release from Parvalbumin-Positive Interneurons}, volume={34}, ISSN={0270-6474 1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.1222-14.2014}, DOI={10.1523/jneurosci.1222-14.2014}, abstractNote={Accumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1α in the brain have remained enigmatic. Previous data demonstrate that PGC-1α is primarily concentrated in inhibitory neurons and that PGC-1α is required for the expression of the interneuron-specific Ca2+-binding protein parvalbumin (PV) throughout the cortex. To identify other possible transcriptional targets of PGC-1α in neural tissue, we conducted a microarray on neuroblastoma cells overexpressing PGC-1α, mined results for genes with physiological relevance to interneurons, and measured cortical gene and protein expression of these genes in mice with underexpression and overexpression of PGC-1α. We observed bidirectional regulation of novel PGC-1α-dependent transcripts spanning synaptic [synaptotagmin 2 (Syt2) and complexin 1 (Cplx1)], structural [neurofilament heavy chain (Nefh)], and metabolic [neutral cholesterol ester hydrolase 1 (Nceh1), adenylate kinase 1 (Ak1), inositol polyphosphate 5-phosphatase J (Inpp5j), ATP synthase mitochondrial F1 complex O subunit (Atp5o), phytanol-CoA-2hydroxylase (Phyh), and ATP synthase mitrochondrial F1 complex α subunit 1 (Atp5a1)] functions. The neuron-specific genes Syt2, Cplx1, and Nefh were developmentally upregulated in an expression pattern consistent with that of PGC-1α and were expressed in cortical interneurons. Conditional deletion of PGC-1α in PV-positive neurons significantly decreased cortical transcript expression of these genes, promoted asynchronous GABA release, and impaired long-term memory. Collectively, these data demonstrate that PGC-1α is required for normal PV-positive interneuron function and that loss of PGC-1α in this interneuron subpopulation could contribute to cortical dysfunction in disease states.}, number={43}, journal={Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Lucas, E. K. and Dougherty, S. E. and McMeekin, L. J. and Reid, C. S. and Dobrunz, L. E. and West, A. B. and Hablitz, J. J. and Cowell, R. M.}, year={2014}, month={Oct}, pages={14375–14387} }
 @article{shan_lucas_drummond_haroutunian_meador-woodruff_mccullumsmith_2013, title={Abnormal expression of glutamate transporters in temporal lobe areas in elderly patients with schizophrenia}, volume={144}, ISSN={0920-9964}, url={http://dx.doi.org/10.1016/j.schres.2012.12.019}, DOI={10.1016/j.schres.2012.12.019}, abstractNote={Glutamate transporters facilitate the buffering, clearance and cycling of glutamate and play an important role in maintaining synaptic and extrasynaptic glutamate levels. Alterations in glutamate transporter expression may lead to abnormal glutamate neurotransmission contributing to the pathophysiology of schizophrenia. In addition, alterations in the architecture of the superior temporal gyrus and hippocampus have been implicated in this illness, suggesting that synapses in these regions may be remodeled from a lifetime of severe mental illness and antipsychotic treatment. Thus, we hypothesize that glutamate neurotransmission may be abnormal in the superior temporal gyrus and hippocampus in schizophrenia. To test this hypothesis, we examined protein expression of excitatory amino acid transporter 1-3 and vesicular glutamate transporter 1 and 2 in subjects with schizophrenia (n=23) and a comparison group (n=27). We found decreased expression of EAAT1 and EAAT2 protein in the superior temporal gyrus, and decreased EAAT2 protein in the hippocampus in schizophrenia. We didn't find any changes in expression of the neuronal transporter EAAT3 or the presynaptic vesicular glutamate transporters VGLUT1-2. In addition, we did not detect an effect of antipsychotic medication on expression of EAAT1 and EAAT2 proteins in the temporal association cortex or hippocampus in rats treated with haloperidol for 9 months. Our findings suggest that buffering and reuptake, but not presynaptic release, of glutamate is altered in glutamate synapses in the temporal lobe in schizophrenia.}, number={1-3}, journal={Schizophrenia Research}, publisher={Elsevier BV}, author={Shan, Dan and Lucas, Elizabeth K. and Drummond, Jana B. and Haroutunian, Vahram and Meador-Woodruff, James H. and McCullumsmith, Robert E.}, year={2013}, month={Mar}, pages={1–8} }
 @article{lucas_dougherty_mcmeekin_trinh_reid_cowell_2012, title={Developmental Alterations in Motor Coordination and Medium Spiny Neuron Markers in Mice Lacking PGC-1α}, volume={7}, ISSN={1932-6203}, url={http://dx.doi.org/10.1371/journal.pone.0042878}, DOI={10.1371/journal.pone.0042878}, abstractNote={Accumulating evidence implicates the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) in the pathophysiology of Huntington Disease (HD). Adult PGC-1α −/− mice exhibit striatal neurodegeneration, and reductions in the expression of PGC-1α have been observed in striatum and muscle of HD patients as well as in animal models of the disease. However, it is unknown whether decreased expression of PGC-1α alone is sufficient to lead to the motor phenotype and striatal pathology characteristic of HD. For the first time, we show that young PGC-1α −/− mice exhibit severe rotarod deficits, decreased rearing behavior, and increased occurrence of tremor in addition to the previously described hindlimb clasping. Motor impairment and striatal vacuolation are apparent in PGC-1α −/− mice by four weeks of age and do not improve or decline by twelve weeks of age. The behavioral and pathological phenotype of PGC-1α −/− mice can be completely recapitulated by conditional nervous system deletion of PGC-1α, indicating that peripheral effects are not responsible for the observed abnormalities. Evaluation of the transcriptional profile of PGC-1α −/− striatal neuron populations and comparison to striatal neuron profiles of R6/2 HD mice revealed that PGC-1α deficiency alone is not sufficient to cause the transcriptional changes observed in this HD mouse model. In contrast to R6/2 HD mice, PGC-1α −/− mice show increases in the expression of medium spiny neuron (MSN) markers with age, suggesting that the observed behavioral and structural abnormalities are not primarily due to MSN loss, the defining pathological feature of HD. These results indicate that PGC-1α is required for the proper development of motor circuitry and transcriptional homeostasis in MSNs and that developmental disruption of PGC-1α leads to long-term alterations in motor functioning.}, number={8}, journal={PLoS ONE}, publisher={Public Library of Science (PLoS)}, author={Lucas, Elizabeth K. and Dougherty, Sarah E. and McMeekin, Laura J. and Trinh, Alisa T. and Reid, Courtney S. and Cowell, Rita M.}, editor={Coleman, Melissa J.Editor}, year={2012}, month={Aug}, pages={e42878} }
 @article{dougherty_reeves_lucas_gamble_lesort_cowell_2012, title={Disruption of Purkinje cell function prior to huntingtin accumulation and cell loss in an animal model of Huntington Disease}, volume={236}, ISSN={0014-4886}, url={http://dx.doi.org/10.1016/j.expneurol.2012.04.015}, DOI={10.1016/j.expneurol.2012.04.015}, abstractNote={Huntington Disease (HD) is a devastating neurological disorder characterized by progressive deterioration of psychiatric, motor, and cognitive function. Purkinje cells (PCs), the output neurons of the cerebellar cortex, have been found to be vulnerable in multiple CAG repeat disorders, but little is known about the involvement of PC dysfunction in HD. To investigate possible PC abnormalities, we performed quantitative real time PCR, Western blot analysis, and immunohistochemistry experiments to explore the changes in PC markers in the R6/2 mouse model of severe HD. There were reductions in the transcript and protein levels of the calcium-binding proteins parvalbumin and calbindin, as well as the enzyme glutamic acid decarboxylase 67. Immunohistochemistry supported these results, with the most substantial changes occurring in the PC layer. To determine whether the reductions in PC marker expression were due to cell loss, we performed stereology on both presymptomatic and end-stage R6/2 mice. Stereological counts indicated a significant reduction in PC number by end-stage but no change in presymptomatic animals (4 weeks of age). To assess cellular function prior to cell loss and symptom onset, we measured spontaneous firing in PCs from 4-week old animals and found a striking deficit in PC firing as indicated by a 57% decrease in spike rate. Interestingly, huntingtin inclusions were not widely observed in PCs until 12 weeks of age, indicating that soluble huntingtin and/or abnormalities in other cell types may contribute to PC dysfunction. Considering the roles for PCs in motor control, these data suggest that early PC dysfunction potentially contributes to motor impairment in this model of HD.}, number={1}, journal={Experimental Neurology}, publisher={Elsevier BV}, author={Dougherty, S.E. and Reeves, J.L. and Lucas, E.K. and Gamble, K.L. and Lesort, M. and Cowell, R.M.}, year={2012}, month={Jul}, pages={171–178} }
 @article{ma_li_lucas_cowell_lin_2010, title={Neuronal Inactivation of Peroxisome Proliferator-activated Receptor γ Coactivator 1α (PGC-1α) Protects Mice from Diet-induced Obesity and Leads to Degenerative Lesions}, volume={285}, ISSN={0021-9258 1083-351X}, url={http://dx.doi.org/10.1074/jbc.m110.151688}, DOI={10.1074/jbc.m110.151688}, abstractNote={Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator that regulates diverse aspects of energy metabolism in peripheral tissues. Mice deficient in PGC-1α have elevated metabolic rate and are resistant to diet-induced obesity. However, it remains unknown whether this alteration in energy balance is due to the action of PGC-1α in peripheral tissues or the central nervous system. In this study, we generated neuronal PGC-1α knock-out mice (BαKO) using calcium/calmodulin-dependent protein kinase IIα (CaMKIIα)-Cre to address its role in the regulation of energy balance and neuronal function. Unlike whole body PGC-1α null mice, BαKO mice have normal adaptive metabolic response to starvation and cold exposure in peripheral tissues. In contrast, BαKO mice are hypermetabolic, and similar to whole body PGC-1α null mice, are also resistant to diet-induced obesity, resulting in significantly improved metabolic profiles. Neuronal inactivation of PGC-1α leads to striatal lesions that are reminiscent of neurodegeneration in whole body PGC-1α null brain and impairs nutritional regulation of hypothalamic expression of genes that regulate systemic energy balance. Together, these studies have demonstrated a physiological role for neuronal PGC-1α in the control of energy balance. Our results also implicate CaMKIIα-positive neurons as an important part of the neural circuitry that governs energy expenditure in vivo.}, number={50}, journal={Journal of Biological Chemistry}, publisher={American Society for Biochemistry & Molecular Biology (ASBMB)}, author={Ma, Di and Li, Siming and Lucas, Elizabeth K. and Cowell, Rita M. and Lin, Jiandie D.}, year={2010}, month={Oct}, pages={39087–39095} }
 @article{lucas_markwardt_gupta_meador-woodruff_lin_overstreet-wadiche_cowell_2010, title={Parvalbumin Deficiency and GABAergic Dysfunction in Mice Lacking PGC-1α}, volume={30}, ISSN={0270-6474 1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.0698-10.2010}, DOI={10.1523/jneurosci.0698-10.2010}, abstractNote={The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of metabolism in peripheral tissues, and it has been proposed that PGC-1α plays a similar role in the brain. Recent evidence suggests that PGC-1α is concentrated in GABAergic interneurons, so we investigated whether male and female PGC-1α −/− mice exhibit abnormalities in interneuron gene expression and/or function. We found a striking reduction in the expression of the Ca2+-binding protein parvalbumin (PV), but not other GABAergic markers, throughout the cerebrum in PGC-1α +/− and −/− mice. Furthermore, PGC-1α overexpression in cell culture was sufficient to robustly induce PV expression. Consistent with a reduction in PV rather than a loss of PV-expressing interneurons, spontaneous synaptic inhibition was not altered in PGC-1α −/− mice. However, evoked synaptic responses displayed less paired-pulse depression and dramatic facilitation in response to repetitive stimulation at the gamma frequency. PV transcript expression was also significantly reduced in retina and heart of PGC-1α −/− animals, suggesting that PGC-1α is required for proper expression of PV in multiple tissues. Together these findings indicate that PGC-1α is a novel regulator of interneuron gene expression and function and a potential therapeutic target for neurological disorders associated with interneuron dysfunction.}, number={21}, journal={Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Lucas, E. K. and Markwardt, S. J. and Gupta, S. and Meador-Woodruff, J. H. and Lin, J. D. and Overstreet-Wadiche, L. and Cowell, R. M.}, year={2010}, month={May}, pages={7227–7235} }
 @article{schwebel_lucas_pearson_2009, title={Do Visually Salient Stimuli Reduce Children’s Risky Decisions?}, volume={16}, ISSN={1068-9583 1573-3572}, url={http://dx.doi.org/10.1007/s10880-009-9161-z}, DOI={10.1007/s10880-009-9161-z}, abstractNote={Children tend to overestimate their physical abilities, and that tendency is related to risk for unintentional injury. This study tested whether or not children estimate their physical ability differently when exposed to stimuli that were highly visually salient due to fluorescent coloring. Sixty-nine 6-year-olds judged physical ability to complete laboratory-based physical tasks. Half judged ability using tasks that were painted black; the other half judged the same tasks, but the stimuli were striped black and fluorescent lime-green. Results suggest the two groups judged similarly, but children took longer to judge perceptually ambiguous tasks when those tasks were visually salient. In other words, visual salience increased decision-making time but not accuracy of judgment. These findings held true after controlling for demographic and temperament characteristics.}, number={3}, journal={Journal of Clinical Psychology in Medical Settings}, publisher={Springer Science and Business Media LLC}, author={Schwebel, David C. and Lucas, Elizabeth K. and Pearson, Alana}, year={2009}, month={Apr}, pages={223–232} }
 @article{schwebel_tavares_lucas_bowling_hodgens_2007, title={Unintentional Injury Risk in Children with Externalizing Behavior Disorders at Summer Camp}, volume={14}, ISSN={1068-9583 1573-3572}, url={http://dx.doi.org/10.1007/s10880-007-9058-7}, DOI={10.1007/s10880-007-9058-7}, number={2}, journal={Journal of Clinical Psychology in Medical Settings}, publisher={Springer Science and Business Media LLC}, author={Schwebel, David C. and Tavares, Casie L. and Lucas, Elizabeth K. and Bowling, Elizabeth B. and Hodgens, J. Bart}, year={2007}, month={Jun}, pages={145–151} }