Regional sex differences in neurochemical profiles of healthy mice measured by magnetic resonance spectroscopy at 9.4 tesla.

Objective: To determine sex differences in the neurochemical concentrations measured by in vivo proton magnetic resonance spectroscopy (1H MRS) of healthy mice on a genetic background commonly used for neurodegenerative disease models. Methods: 1H MRS data collected from wild type mice with C57BL/6 or related genetic backgrounds in seven prior studies were used in this retrospective analysis. To be included, data had to be collected at 9.4 tesla magnetic field using advanced 1H MRS protocols, with isoflurane anesthesia and similar animal handling protocols, and a similar number of datasets from male and female mice had to be available for the brain regions analyzed. Overall, 155 spectra from female mice and 166 spectra from male mice (321 in total), collected from six brain regions (brainstem, cerebellum, cortex, hippocampus, hypothalamus, and striatum) at various ages were included. Results: Concentrations of taurine, total creatine (creatine + phosphocreatine), ascorbate, glucose and glutamate were consistently higher in male vs. female mice in most brain regions. Striatum was an exception with similar total creatine in male and female mice. The sex difference pattern in the hypothalamus was notably different from other regions. Interaction between sex and age was significant for total creatine and taurine in the cerebellum and hippocampus. Conclusion: Sex differences in regional neurochemical levels are small but significant and age-dependent, with consistent male-female differences across most brain regions. The neuroendocrine region hypothalamus displays a different pattern of sex differences in neurochemical levels. Differences in energy metabolism and cellular density may underlie the differences, with higher metabolic rates in females and higher osmoregulatory and antioxidant capacity in males.

Connecting the Dots from Professional Development to Student Learning.

Following professional development (PD), implementation of contemporary topics into high school biology requires teachers to make critical decisions regarding integration of novel content into existing course scope and sequence. Often exciting topics, such as neuroscience, do not perfectly align with standards. Despite commitment to enacting what was learned in the PD, teachers must adapt novel content to their perceptions of good teaching, local context, prior knowledge of their students, and state and district expectations. How teachers decide to integrate curricula encountered from PD programs may affect student outcomes. This mixed-methods study examined the relationship between curricular application strategies following an inquiry-based neuroscience PD and student learning. Post-PD curricular implementation was measured qualitatively through analysis of teacher action plans and classroom observations and quantitatively using hierarchical linear modeling to determine the impact of implementation on student performance. Participation in neuroscience PD predicted improved student learning compared with control teachers. Of the two distinct curricular implementation strategies, enacting a full unit produced significantly greater student learning than integrating neuroscience activities into existing biology units. Insights from this analysis should inform teacher implementation of new curricula after PD on other contemporary biology topics.

Neuroscience Concepts Changed Teachers' Views of Pedagogy and Students.

Advances in neuroscience reveal how individual brains change as learning occurs. Translating this neuroscience into practice has largely been unidirectional, from researchers to teachers. However, how teachers view and incorporate neuroscience ideas in their classroom practices remains relatively unexplored. Previously fourteen non-science teachers participated in a 3-week three credit graduate course focusing on foundational ideas in neuroscience. The current work was undertaken to gain insight into if and how individual teachers choose to later apply the proposed set of educational neuroscience concepts (ENCs) in their classrooms. This qualitative follow-up study examined commonalities in how teachers of diverse ages and subjects utilized their new neuroscience understandings. To this end, a year after the course, all participants assessed their perceived usefulness of the ENCs in a survey. Six of those teachers permitted classroom observations and participated in interviews that focused on how the ENCs may have influenced their lesson planning and teaching. The survey revealed that irrespective of subject areas or grade levels taught, teachers found the ENCs useful as organizing principles for their pedagogy now and in the future. Overall teachers estimated that the ENCs' influence on lesson design had increased from 51% prior to the course to an estimated 90% for future lessons. A cross-case analysis of classroom observations and interviews revealed how teachers used ENCs to inform their pedagogical decisions, organize actions in their classroom, influence their understanding of students, and respond to individual contexts. Teachers recognized the importance of student agency for engaging them in the learning process. The ENCs also offered teachers explanations that affirmed known practices or helped justify exploring untried techniques. The foundational neuroscience concepts offered a small group of teachers a lens to reconsider, re-envision and re-design their lessons. Some teachers applied these ideas more broadly or frequently than others. This case study provided insights into how teachers can directly apply neuroscience knowledge to their practice and views of students.

Training-of-Trainers Neuroscience and Mental Health Teacher Education in Liberia Improves Self-Reported Support for Students.

Education programs have been central to reestablishing social norms, rebuilding public educational institutions, and addressing public attitudes toward mental illness in Liberia following a protracted civil war and the Ebola epidemic. The aim of this study was to determine if a program combining an understanding of neuroscience with mental health literacy content could increase teachers' awareness of students' mental health issues and produce changes in teacher attitudes and classroom practices. A tiered Training-of-Trainers approach was employed. The first workshop trained 24 Liberian secondary science teachers in the neurobiology of learning, memory, emotions, stress and adolescent brain development. A Leadership Team formed from eight of the Tier I participants then adapted the curriculum, added in more mental health literacy content and led four Tier II workshops and four follow-up Refresher sessions. Participants completed a neuroscience knowledge test and surveys assessing stigma, general perceptions of people with mental illness, and burnout. A subset of Tier II teachers participated in a structured interview at the Refresher time point. Teachers in both tiers acquired basic neuroscience knowledge. Tier I, but not Tier II teachers significantly improved their surveyed attitudes toward people with mental illness. No changes were found in overall teacher burnout. Despite these survey results, the interviewed Tier II teachers self-reported behavioral changes in how they approached their teaching and students in their classrooms. Interviewees described how they now understood social and emotional challenges students might be experiencing and recognized abnormal behaviors as having a biopsychosocial basis. Teachers reported reduced use of verbal and corporal punishment and increased positive rewards systems, such as social and emotional support for students through building relationships. Refresher discussions concurred with the interviewees. In contrast to previous teacher mental health literacy programs which did not bring about a change in helping behaviors, this pilot program may have been successful in changing teacher knowledge and self-reported behaviors, improving teacher-student relationships and decreasing harsh discipline. The combination of basic neuroscience concepts with training on how to recognize mental health issues and refer students should be investigated further as a strategy to promote teacher mental health literacy.

Tiered Neuroscience and Mental Health Professional Development in Liberia Improves Teacher Self-Efficacy, Self-Responsibility, and Motivation.

After acquiring knowledge of the neuroscience of learning, memory, stress and emotions, teachers incorporate more cognitive engagement and student-centered practices into their lessons. However, the role understanding neuroscience plays in teachers own affective and motivational competencies has not yet been investigated. The goal of this study was to investigate how learning neuroscience effected teachers' self-efficacy, beliefs in their ability to teach effectively, self-responsibility and other components of teacher motivation. A pilot training-of-trainers program was designed and delivered in Liberia combining basic neuroscience with information on social, emotional, behavioral and mental health issues faced by students. Tier I of the professional development was a 2 weeks workshop led by a visiting neuroscientist. A subset of the 24 Tier I secondary science teachers formed a Leadership Team who adapted the content to the Liberian context and subsequently led additional workshops and follow-up sessions for the Tier II secondary science teachers. Science teachers in both tiers completed the affective-motivational scales from the internationally vetted, multiscale Innovative Teaching for Effective Learning Teacher Knowledge Survey from the OECD. Tier II teachers completed the survey in a pre-post-delayed post design. Tier I teachers completed the survey after the workshop with their attitudes at that time and separately with retrospective projections of their pre-workshop attitudes. Ten of the 92 Tier II teachers participated in structured interviews at follow-up. Statistical analysis of survey data demonstrated improved teacher self-efficacy, self-responsibility for student outcomes, and motivation to teach. Qualitatively, teachers expressed more confidence in their ability to motivate students, engage them through active learning, and manage the class through positive rather than negative reinforcement. Teachers' own self-regulation improved as they made efforts to build supporting relationships with students. Together, these results demonstrated that (i) teacher affective-motivational attitudes can be altered with professional development, (ii) basic neuroscience, as knowledge of how students learn, can improve teacher competency, and (iii) a training-of-trainers model can be effective in a low and middle income country for disseminating neuroscience knowledge, increasing teachers' knowledge of students' social and emotional needs, and promoting educational improvement.

Contributions of Neuroscience Knowledge to Teachers and Their Practice.

While neuroscience has elucidated the mechanisms underpinning learning and memory, accurate dissemination of this knowledge to teachers and educators has been limited. This review focuses on teacher professional development in neuroscience that harnessed the power of active-learning strategies and best educational practices resulting in increased teacher and student understanding of cognition and brain function. For teachers, the experience of learning a novel subject in an active manner enabled them to subsequently teach using similar strategies. Most important, participants viewed neuroscience as a frame for understanding why active-learning pedagogies work to engage and motivate students. Teachers themselves made connections applying neuroscience concepts to understand why learner-centered pedagogies are effective in promoting higher order thinking and deep learning in their students. Teachers planned and embraced pedagogies involving modeling, experimentation, discussion, analysis, and synthesis, increasing classroom cognitive engagement. Comprehending that everyone is in charge of changing their own brains is a tremendously powerful idea that may motivate science and non-science teachers to provide students opportunities to actively engage with content. Neuroscience courses for preservice and in-service teachers, provided as collaborations between scientists and teacher educators, can result in improved science education, pedagogy, and understanding of neuroscience.

Taking an educational psychology course improves neuroscience literacy but does not reduce belief in neuromyths.

Educators are increasingly interested in applying neuroscience findings to improve educational practice. However, their understanding of the brain often lags behind their enthusiasm for the brain. We propose that educational psychology can serve as a bridge between basic research in neuroscience and psychology on one hand and educational practice on the other. We evaluated whether taking an educational psychology course is associated with increased neuroscience literacy and reduced belief in neuromyths in a sample of South Korean pre-service teachers. The results showed that taking an educational psychology course was associated with the increased neuroscience literacy, but there was no impact on belief in neuromyths. We consider the implications of these and other findings of the study for redesigning educational psychology courses and textbooks for improving neuroscience literacy.

Learning Neuroscience with Technology: A Scaffolded, Active Learning Approach.

Mobile applications (apps) for learning technical scientific content are becoming increasingly popular in educational settings. Neuroscience is often considered complex and challenging for most students to understand conceptually. iNeuron is a recently developed iOS app that teaches basic neuroscience in the context of a series of scaffolded challenges to create neural circuits and increase understanding of nervous system structure and function. In this study, four different ways to implement the app within a classroom setting were explored. The goal of the study was to determine the app's effectiveness under conditions closely approximating real-world use, and to evaluate whether collaborative play and student-driven navigational features contributed to its effectiveness. Students used the app either individually or in small groups, and used a version with either a fixed or variable learning sequence. Student performance on a pre- and post- neuroscience content assessment was analyzed and compared between students who used the app and a control group receiving standard instruction, and logged app data were analyzed. Significantly greater learning gains were found for all students who used the app compared to control. All four implementation modes were effective in producing student learning gains relative to controls, but did not differ in their effectiveness to one another. In addition, students demonstrated transfer of information learned in one context to another within the app. These results suggest that teacher-led neuroscience instruction can be effectively supported by a scaffolded, technology-based curriculum which can be implemented in multiple ways to enhance student learning.

Towards an Understanding of Energy Impairment in Huntington's Disease Brain.

This review systematically examines the evidence for shifts in flux through energy generating biochemical pathways in Huntington's disease (HD) brains from humans and model systems. Compromise of the electron transport chain (ETC) appears not to be the primary or earliest metabolic change in HD pathogenesis. Rather, compromise of glucose uptake facilitates glucose flux through glycolysis and may possibly decrease flux through the pentose phosphate pathway (PPP), limiting subsequent NADPH and GSH production needed for antioxidant protection. As a result, oxidative damage to key glycolytic and tricarboxylic acid (TCA) cycle enzymes further restricts energy production so that while basal needs may be met through oxidative phosphorylation, those of excessive stimulation cannot. Energy production may also be compromised by deficits in mitochondrial biogenesis, dynamics or trafficking. Restrictions on energy production may be compensated for by glutamate oxidation and/or stimulation of fatty acid oxidation. Transcriptional dysregulation generated by mutant huntingtin also contributes to energetic disruption at specific enzymatic steps. Many of the alterations in metabolic substrates and enzymes may derive from normal regulatory feedback mechanisms and appear oscillatory. Fine temporal sequencing of the shifts in metabolic flux and transcriptional and expression changes associated with mutant huntingtin expression remain largely unexplored and may be model dependent. Differences in disease progression among HD model systems at the time of experimentation and their varying states of metabolic compensation may explain conflicting reports in the literature. Progressive shifts in metabolic flux represent homeostatic compensatory mechanisms that maintain the model organism through presymptomatic and symptomatic stages.

Oxygen consumption deficit in Huntington disease mouse brain under metabolic stress.

In vivo evidence for brain mitochondrial dysfunction in animal models of Huntington disease (HD) is scarce. We applied the novel 17O magnetic resonance spectroscopy (MRS) technique on R6/2 mice to directly determine rates of oxygen consumption (CMRO2) and assess mitochondrial function in vivo Basal respiration and maximal CMRO2 in the presence of the mitochondrial uncoupler dinitrophenol (DNP) were compared using 16.4 T in isoflurane anesthetized wild type (WT) and HD mice at 9 weeks. At rest, striatal CMRO2 of R6/2 mice was equivalent to that of WT, indicating comparable mitochondrial output despite onset of motor symptoms in R6/2. After DNP injection, the maximal CMRO2 in both striatum and cortex of R6/2 mice was significantly lower than that of WT, indicating less spare energy generating capacity. In a separate set of mice, oligomycin injection to block ATP generation decreased CMRO2 equally in brains of R6/2 and WT mice, suggesting oxidative phosphorylation capacity and respiratory coupling were equivalent at rest. Expression levels of representative mitochondrial proteins were compared from harvested tissue samples. Significant differences between R6/2 and WT included: in striatum, lower VDAC and the mitochondrially encoded cytochrome oxidase subunit I relative to actin; in cortex, lower tricarboxylic acid cycle enzyme aconitase and higher protein carbonyls; in both, lower glycolytic enzyme enolase. Therefore in R6/2 striatum, lowered CMRO2 may be attributed to a decrease in mitochondria while the cortical CMRO2 decrease may result from constraints upstream in energetic pathways, suggesting regionally specific changes and possibly rates of metabolic impairment.

Brivaracetam augments short-term depression and slows vesicle recycling.

OBJECTIVE: Brivaracetam (BRV) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A (SV2A) with a higher affinity than the antiepileptic drug levetiracetam (LEV). Experiments were performed to determine if BRV acted similarly to LEV to induce or augment short-term depression (STD) under high-frequency neuronal stimulation and slow synaptic vesicle recycling. METHODS: Electrophysiologic field excitatory postsynaptic potential (fEPSP) recordings were made from CA1 synapses in rat hippocampal slices loaded with BRV or LEV during intrinsic activity or with BRV actively loaded during hypertonic stimulation. STD was examined in response to 5 or 40 Hz stimulus trains. Presynaptic release of FM1-43 was visualized using two-photon microscopy to assess drug effects upon synaptic vesicle mobilization. RESULTS: When hippocampal slices were incubated in 0.1-30 µm BRV or 30 µm-1 mm LEV for 3 h, the relative CA1 field EPSPs decreased over the course of a high-frequency train of stimuli more than for control slices. This STD was frequency- and concentration-dependent, with BRV being 100-fold more potent than LEV. The extent of STD depended on the length of the incubation time for both drugs. Pretreatment with LEV occluded the effects of BRV. Repeated hypertonic sucrose treatments and train stimulation successfully unloaded BRV from recycling vesicles and reversed BRVs effects on STD, as previously reported for LEV. At their maximal concentrations, BRV slowed FM1-43 release to a greater extent than in slices loaded with LEV during prolonged stimulation. SIGNIFICANCE: BRV, similar to LEV, entered into recycling synaptic vesicles and produced a frequency-dependent decrement of synaptic transmission at 100-fold lower concentrations than LEV. In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV, suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV2A to curb synaptic transmission and limit epileptic activity.

Seletracetam enhances short term depression in vitro.

Seletracetam (SEL), an analog of the antiepileptic drug levetiracetam (LEV), decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle protein SV2A with a higher affinity than LEV. Experiments were performed to determine if SEL, like LEV, reduces the later EPSPs in long trains of stimuli in a manner dependent upon access to the interior of synaptic vesicles and SV2A binding. When hippocampal slices were incubated in 3-30µM SEL for 3h, but not 30 min, the relative amplitude of the CA1 field excitatory synaptic potentials decreased over the course of a train of high frequency stimuli more than for control slices. This short term depression was frequency and dose dependent and largely disappeared when the spontaneous activity during the loading period was removed by cutting the Schaffer collaterals. The SEL effect was also observed in slices loaded during prolonged stimulation at 1Hz, but not 10Hz. Hippocampal slices loaded with both SEL and FM1-43 to visualize synaptic boutons released the FM1-43 in response to prolonged stimulation much more slowly than control slices during prolonged stimulation. Like LEV, SEL produced a frequency-dependent decrement of synaptic transmission that was dependent upon the drug entering recycling synaptic vesicles and compatible with SV2A binding. Previous observations of SV2A binding affinity correlated with the current effect of SEL and the previously reported effect of LEV on synaptic transmission validate SV2A as an extremely attractive target for future antiepileptic drug development.

Active learning in a neuroethics course positively impacts moral judgment development in undergraduates.

The growing neuroscientific understanding of the biological basis of behaviors has profound social and ethical implications. To address the need for public awareness of the consequences of these advances, we developed an undergraduate neuroethics course, Neuroscience and Society, at the University of Minnesota. Course evolution, objectives, content, and impact are described here. To engage all students and facilitate undergraduate ethics education, this course employed daily reading, writing, and student discussion, case analysis, and team presentations with goals of fostering development of moral reasoning and judgment and introducing application of bioethical frameworks to topics raised by neuroscience. Pre- and post-course Defining Issues Test (DIT) scores and student end-of-course reflections demonstrated that course objectives for student application of bioethical frameworks to neuroethical issues were met. The active-learning, student-centered pedagogical approaches used to achieve these goals serve as a model for how to effectively teach neuroethics at the undergraduate level.

Neuroscientists' classroom visits positively impact student attitudes.

The primary recommendation of the 2010 President's Council of Advisors on Science and Technology report on K-12 education was to inspire more students so that they are motivated to study science. Scientists' visits to classrooms are intended to inspire learners and increase their interest in science, but verifications of this impact are largely qualitative. Our primary goal was to evaluate the impact of a longstanding Brain Awareness classroom visit program focused on increasing learners understanding of their own brains. Educational psychologists have established that neuroscience training sessions can improve academic performance and shift attitudes of students from a fixed mindset to a growth mindset. Our secondary goal was to determine whether short interactive Brain Awareness scientist-in-the-classroom sessions could similarly alter learners' perceptions of their own potential to learn. Teacher and student surveys were administered in 4(th)-6(th) grade classrooms throughout Minnesota either before or after one-hour Brain Awareness sessions that engaged students in activities related to brain function. Teachers rated the Brain Awareness program as very valuable and said that the visits stimulated students' interest in the brain and in science. Student surveys probed general attitudes towards science and their knowledge of neuroscience concepts (particularly the ability of the brain to change). Significant favorable improvements were found on 10 of 18 survey statements. Factor analyses of 4805 responses demonstrated that Brain Awareness presentations increased positive attitudes toward science and improved agreement with statements related to growth mindset. Overall effect sizes were small, consistent with the short length of the presentations. Thus, the impact of Brain Awareness presentations was positive and proportional to the efforts expended, demonstrating that short, scientist-in-the-classroom visits can make a positive contribution to primary school students' attitudes toward science and learning.

Non-invasive measurement of cerebral oxygen metabolism in the mouse brain by ultra-high field (17)O MR spectroscopy.

To assess cerebral energetics in transgenic mouse models of neurologic disease, a robust, efficient, and practical method for quantification of cerebral oxygen consumption is needed. (17)O magnetic resonance spectroscopy (MRS) has been validated to measure cerebral metabolic rate of oxygen (CMRO2) in the rat brain; however, mice present unique challenges because of their small size. We show that CMRO2 measurements with (17)O MRS in the mouse brain are highly reproducible using 16.4 Tesla and a newly designed oxygen delivery system. The method can be utilized to measure mitochondrial function in mice quickly and repeatedly, without oral intubation, and has numerous potential applications to study cerebral energetics.

Decreased expression of GLT-1 in the R6/2 model of Huntington's disease does not worsen disease progression.

Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease (HD). Glutamate is the predominant excitatory neurotransmitter in the brain, and excess activation of glutamate receptors can cause neuronal dysfunction and death. Glutamate transporters regulate the extracellular concentration of glutamate. GLT-1 is the most abundant glutamate transporter, and accounts for most of the glutamate transport in the brain. Administration of ceftriaxone, an antibiotic that increases the functional expression of GLT-1, can improve the behavioral phenotype of the R6/2 mouse model of HD. To test the hypothesis that GLT-1 expression critically affects the HD disease process, we generated a novel mouse model that is heterozygous for the null allele of GLT-1 and carries the R6/2 transgene (double mutation). We demonstrated that the protein expression of total GLT-1, as well as two of its isoforms, is decreased within the cortex and striatum of 12-week-old R6/2 mice, and that the expression of EAAC1 was decreased in the striatum. Protein expression of GLT-1 was further decreased in the cortex and striatum of the double mutation mice compared with the R6/2 mice at 11 weeks. However, the effects of the R6/2 transgene on weight loss, accelerating rotarod, climbing and paw-clasping were not exacerbated in these double mutants. Na(+) -dependent glutamate uptake into synapatosomes isolated from the striatum and cortex of 11-week-old R6/2 mice was unchanged compared with controls. These results suggest that changes in GLT-1 expression or function per se are unlikely to potentiate or ameliorate the progression of HD.

Infusing Neuroscience into Teacher Professional Development.

Bruer (1997) advocated connecting neuroscience and education indirectly through the intermediate discipline of psychology. We argue for a parallel route: the neurobiology of learning, and in particular the core concept of plasticity, have the potential to directly transform teacher preparation and professional development, and ultimately to affect how students think about their own learning. We present a case study of how the core concepts of neuroscience can be brought to in-service teachers - the BrainU workshops. We then discuss how neuroscience can be meaningfully integrated into pre-service teacher preparation, focusing on institutional and cultural barriers.

Homeostatic adaptations in brain energy metabolism in mouse models of Huntington disease.

Impairment of energy metabolism is a key feature of Huntington disease (HD). Recently, we reported longitudinal neurochemical changes in R6/2 mice measured by in-vivo proton magnetic resonance spectroscopy ((1)H MRS; Zacharoff et al, 2012). Here, we present similar (1)H MRS measurements at an early stage in the milder Q111 mouse model. In addition, we measured the concentration of ATP and inorganic phosphate (P(i)), key energy metabolites not accessible with (1)H MRS, using (31)P MRS both in Q111 and in R6/2 mice. Significant changes in striatal creatine and phosphocreatine were observed in Q111 mice at 6 weeks relative to control, and these changes were largely reversed at 13 weeks. No significant change was detected in ATP concentration, in either HD mouse, compared with control. Calculated values of [ADP], phosphorylation potential, relative rate of ATP synthase (v/V(max)(ATP)), and relative rate of creatine kinase (v/V(max)(CK)) were calculated from the measured data. ADP concentration and v/V(max)(ATP) were increased in Q111 mice at 6 weeks, and returned close to normal at 13 weeks. In contrast, these parameters were normal in R6/2 mice. These results suggest that early changes in brain energy metabolism are followed by compensatory shifts to maintain energetic homeostasis from early ages through manifest disease.

Cortical metabolites as biomarkers in the R6/2 model of Huntington's disease.

To improve the ability to move from preclinical trials in mouse models of Huntington's disease (HD) to clinical trials in humans, biomarkers are needed that can track similar aspects of disease progression across species. Brain metabolites, detectable by magnetic resonance spectroscopy (MRS), have been suggested as potential biomarkers in HD. In this study, the R6/2 transgenic mouse model of HD was used to investigate the relative sensitivity of the metabolite profiling and the brain volumetry to anticipate the disease progression. Magnetic resonance imaging (MRI) and (1)H MRS data were acquired at 9.4 T from the R6/2 mice and wild-type littermates at 4, 8, 12, and 15 weeks. Brain shrinkage was detectable in striatum, cortex, thalamus, and hypothalamus by 12 weeks. Metabolite changes in cortex paralleled and sometimes preceded those in striatum. The entire set of metabolite changes was compressed into principal components (PCs) using Partial Least Squares-Discriminant Analysis (PLS-DA) to increase the sensitivity for monitoring disease progression. In comparing the efficacy of volume and metabolite measurements, the cortical PC1 emerged as the most sensitive single biomarker, distinguishing R6/2 mice from littermates at all time points. Thus, neurochemical changes precede volume shrinkage and become potential biomarkers for HD mouse models.