Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knockout mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.The subthalamic nucleus (STN) has long been a structure of interest for researchers and clinicians alike. There is ample evidence that high-frequency stimulation of the STN improves symptoms such as tremor, rigidity, and slowness of movement, so called bradykinesia, in patients with Parkinson disease (see ref. 1 for review), but the mechanism through which this is achieved is still unknown. Some studies suggest that electrical stimulation causes a hyperexcitation of this structure (2), whereas others find evidence that the opposite is true (3–5). Other possible interpretations include the activation of the zona incerta, a neighboring white-matter structure (6) or of fibers coming from the motor cortex (7). Bilateral lesions of the STN improve locomotion (8), a result that is consistent with the inactivation hypothesis. However, previous studies have also found cognitive side effects when using high-frequency stimulation of the STN (9), findings supported by lesion studies in experimental animals, which led to abnormalities in operant tasks involving attention and impulsivity (10, 11). The projections of the STN to other regions help explain the multiple roles of this structure: It sends projections to other targets in the basal ganglia, such as the internal segment of the globus pallidus [also termed the entopeduncular nucleus (EP) in rodents] and the substantia nigra pars reticulata (SNr) (12, 13). The STN is also part of a circuit that includes the prefrontal cortex and the nucleus accumbens (14). It is currently unknown, however, whether these different roles reflect a heterogeneous population of cells, characterized by distinct gene expression. If that is the case, it would allow direct control over each cell population, facilitating the investigation of their respective roles. In rodents, the STN is believed to be composed solely of glutamatergic neurons, characterized by expression of the subtype 2 Vesicular glutamate transporter (Vglut2), whereas the other two subtypes (Vglut1 and Vglut3) have not been detected (15, 16). Selective targeted deletion of Vglut2 expression in this nucleus would therefore provide a specific loss-of-function model that would bypass a common problem presented by traditional lesions with pharmacological agents, which have patterns of diffusion that likely affect surrounding structures (17). It is known, however, that Vglut2 is expressed in many other parts of the brain (18), and a complete knockout in the mouse is not viable (19, 20). There is also evidence that the promoter driving expression of the Paired-like homeodomain 2 (Pitx2) gene is strong in the mouse STN (21) but is also not specific to this structure and a full knockout of Pitx2 expression results in premature death (22). To achieve the desired level of specificity, using a conditional knockout technique previously used to eliminate glutamatergic transmission in other cell types (23), we crossed Pitx2-Cre and Vglut2-lox mice, producing Vglut2^{f/f;Pitx2-Cre} conditional knockout (cKO) mice in which Vglut2 expression in the STN was strongly reduced in comparison with expression levels in littermate control mice. To understand the physiological contribution of the selected subpopulation of STN cells, we characterized these cKO mice with regard to anatomical, electrophysiological, and molecular properties, as well as their performance in a range of behavioral tasks.     

Context and dating of Aurignacian vulvar representations from Abri Castanet, France

We report here on the 2007 discovery, in perfect archaeological context, of part of the engraved and ocre-stained undersurface of the collapsed rockshelter ceiling from Abri Castanet, Dordogne, France. The decorated surface of the 1.5-t roof-collapse block was in direct contact with the exposed archaeological surface onto which it fell. Because there was no sedimentation between the engraved surface and the archaeological layer upon which it collapsed, it is clear that the Early Aurignacian occupants of the shelter were the authors of the ceiling imagery. This discovery contributes an important dimension to our understanding of the earliest graphic representation in southwestern France, almost all of which was discovered before modern methods of archaeological excavation and analysis. Comparison of the dates for the Castanet ceiling and those directly obtained from the Chauvet paintings reveal that the "vulvar" representations from southwestern France are as old or older than the very different wall images from Chauvet.     

Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2

The stem cell-intrinsic model of self-renewal via asymmetric cell division (ACD) posits that fate determinants be partitioned unequally between daughter cells to either activate or suppress the stemness state. ACD is a purported mechanism by which hematopoietic stem cells (HSCs) self-renew, but definitive evidence for this cellular process remains open to conjecture. To address this issue, we chose 73 candidate genes that function within the cell polarity network to identify potential determinants that may concomitantly alter HSC fate while also exhibiting asymmetric segregation at cell division. Initial gene-expression profiles of polarity candidates showed high and differential expression in both HSCs and leukemia stem cells. Altered HSC fate was assessed by our established in vitro to in vivo screen on a subcohort of candidate polarity genes, which revealed 6 novel positive regulators of HSC function: Ap2a2, Gpsm2, Tmod1, Kif3a, Racgap1, and Ccnb1. Interestingly, live-cell videomicroscopy of the endocytic protein AP2A2 shows instances of asymmetric segregation during HSC/progenitor cell cytokinesis. These results contribute further evidence that ACD is functional in HSC self-renewal, suggest a role for Ap2a2 in HSC activity, and provide a unique opportunity to prospectively analyze progeny from HSC asymmetric divisions.     

High Mortality in Late Octogenarians Undergoing Isolated Aortic Valve Replacement for Aortic Valve Stenosis: EuroSCORE Underestimates Mortality in this Cohort

Objectives Considering the expanding technology of catheter-based aortic valve implantation, high-risk patients who would not be suitable for conventional aortic valve replacement (AVR) should be identified.Methods From 1997 to April 2007, 190 patients aged from 80 and 89 years old received isolated AVR. Patients between 80 and 84 years old were categorized as the early octogenarians (n = 148) and patients between 85 and 89 years old were categorized as the late octogenarians (n = 42).Results Thirty days mortality in the early and late octogenarians were 6 and 21%, respectively (p = 0.003). The additive and logistic EuroSCORE were 8.0 ± 2.4 and 8.8 ± 1.8 in the early octogenarians and 13.2 ± 11.8 and 14.6 ± 8.7 in the late octogenarians. Multivariate analysis revealed the late octogenarians (OR 6.7, 95%CL 1.8-24.4, p = 0.004) and poor left ventricular function (OR 8.0, 95%CL 1.2-53.5, p = 0.032) as significant risk factors for 30 days mortality. Early octogenarians showed 1-year, 3-year, 5-year, and 8-year survival of 82.4, 67.6, 54.7, and 33%, respectively. Late octogenarians showed 1-year, 3-year, 5-year, and 8-year survivals of 69.0, 66.2, 41.6, 22.3%, respectively.Conclusions Mortality after AVR in the late octogenarians was very high, and was underestimated by EuroSCORE in this patients group. In late octogenarians, catheter-based aortic valve implantation despite relative low EuroSCORE level could be considered as a reasonable alternative.     

A Case of an Arachnoid Cyst Masquerading as Corticobasal Degeneration

We present an individual, “JD”, a 69-year-old Caucasian, married female with symptoms that included progressive right arm stiffness, tremor, and clumsiness; increasing gait and balance disturbance; increased fatigue and emotionality. Neuropsychological evaluation revealed compromised semantics and language-associated functions; impaired visual constructional ability; markedly reduced cognitive and visuomotor processing speed; low average to average working memory; variable praxis performance; variable abstract reasoning, problem solving, and set shifting; and lower overall intellectual functioning compared to premorbid estimates. Overall, her neuropsychological profile indicated marked compromise of the frontal and left parietal regions. The data coupled with her symptom pattern and demographics partially fit corticobasal degeneration diagnostic criteria. Neuroimaging, however, performed 2 years prior to the assessment and again during the current workup revealed an enlarging arachnoid cyst compressing the left parietal and posterior frontal lobe and a small portion of the right medial frontal-parietal region. We discuss the neuroanatomical substrates involved in her cognitive presentation and how two very distinct pathological processes (corticobasal degeneration, arachnoid cyst) can result in two similar symptom presentations. We summarize how multidisciplinary assessment assists with differential diagnosis and treatment planning.