Divergent topographic projection of cerebral cortical areas to overlapping cerebellar lobules through distinct regions of the pontine nuclei.

The massive axonal projection from the cerebrum to the cerebellum through the pontine nuclei supports the cerebrocerebellar coordination of motor and nonmotor functions. However, the cerebrum and cerebellum have distinct patterns of functional localization in their cortices. We addressed this issue by bidirectional neuronal tracing from 22 various locations of the pontine nuclei in the mouse in a comprehensive manner. Cluster analyses of the distribution patterns of labeled cortical pyramidal cells and cerebellar mossy fiber terminals classified all cases into six groups located in six different subareas of the pontine nuclei. The lateral (insular), mediorostral (cingulate and prefrontal), and caudal (visual and auditory) cortical areas of the cerebrum projected to the medial, rostral, and lateral subareas of the pontine nuclei, respectively. These pontine subareas then projected mainly to the crus I, central vermis, and paraflocculus divergently. The central (motor and somatosensory) cortical areas projected to the centrorostral, centrocaudal and caudal subareas of the pontine nuclei, which then projected mainly to the rostral and caudal lobules with a somatotopic arrangement. The results indicate a new pontine nuclei-centric view of the corticopontocerebellar projection: the generally parallel corticopontine projection to pontine nuclei subareas is relayed to the highly divergent pontocerebellar projection terminating in overlapping specific lobules of the cerebellum. Consequently, the mode of the pontine nuclei relay underlies the cerebellar functional organization.

Acetylcholine waves and dopamine release in the striatum.

Striatal dopamine encodes reward, with recent work showing that dopamine release occurs in spatiotemporal waves. However, the mechanism of dopamine waves is unknown. Here we report that acetylcholine release in mouse striatum also exhibits wave activity, and that the spatial scale of striatal dopamine release is extended by nicotinic acetylcholine receptors. Based on these findings, and on our demonstration that single cholinergic interneurons can induce dopamine release, we hypothesized that the local reciprocal interaction between cholinergic interneurons and dopamine axons suffices to drive endogenous traveling waves. We show that the morphological and physiological properties of cholinergic interneuron - dopamine axon interactions can be modeled as a reaction-diffusion system that gives rise to traveling waves. Analytically-tractable versions of the model show that the structure and the nature of propagation of acetylcholine and dopamine traveling waves depend on their coupling, and that traveling waves can give rise to empirically observed correlations between these signals. Thus, our study provides evidence for striatal acetylcholine waves in vivo, and proposes a testable theoretical framework that predicts that the observed dopamine and acetylcholine waves are strongly coupled phenomena.

Dopamine error signal to actively cope with lack of expected reward.

To obtain more of a particular uncertain reward, animals must learn to actively overcome the lack of reward and adjust behavior to obtain it again. The neural mechanisms underlying such coping with reward omission remain unclear. Here, we developed a task in rats to monitor active behavioral switch toward the next reward after no reward. We found that some dopamine neurons in the ventral tegmental area exhibited increased responses to unexpected reward omission and decreased responses to unexpected reward, following the opposite responses of the well-known dopamine neurons that signal reward prediction error (RPE). The dopamine increase reflected in the nucleus accumbens correlated with behavioral adjustment to actively overcome unexpected no reward. We propose that these responses signal error to actively cope with lack of expected reward. The dopamine error signal thus cooperates with the RPE signal, enabling adaptive and robust pursuit of uncertain reward to ultimately obtain more reward.

Reorganization of longitudinal compartments in the laterally protruding paraflocculus of the postnatal mouse cerebellum.

The paraflocculus and the neighboring smaller flocculus form a remarkable protrusion in the ventrolateral aspect of the mouse cerebellum, in which the longitudinal compartments are conspicuously oriented perpendicularly to the sagittal plane. The developmental process of such anatomical arrangements in these lobules has not been fully clarified. Here, we used the genetic tractability of pcdh10-lacZ knock-in (OL-KO), IP 3 R1-nls-lacZ transgenic (1NM13) and Gpr26cre-Ai9-AldocV mice to track the development of compartments and examined local longitudinal orientation of Purkinje cells within the paraflocculus and flocculus. We observed a distinct pcdh10-positive (pcdh10+) compartment in the flocculus, whereas the paraflocculus and other lobules had a continuous paravermal pcdh10+ compartment, in the embryonic OL-KO cerebellum. During the first postnatal week, the parafloccular pcdh10+ compartment shifted laterally to the most lateral edge in the caudal part of the protruding paraflocculus. Although the most medial edge of the parafloccular pcdh10+ compartment remained in the nonprotruding part of the paraflocculus, it was disrupted from the originally continuous pcdh10+ compartment in the copula pyramidis. The local longitudinal orientation changed gradually along with the mediolateral extent of the copula pyramidis, almost becoming perpendicular to the sagittal plane in the laterally connected paraflocculus in the adult cerebellum. This rotational change in orientation was derived from the short U-shaped embryonic cerebellum, in which the surfaces of the flocculus and paraflocculus were oriented laterally. These results indicated that the peculiar compartmental organization of the paraflocculus originates from the embryonic common hemispheric compartmental organization and shaped by the significant reorganization process in the first postnatal week.

Cerebellar modules in the olivo-cortico-nuclear loop demarcated by pcdh10 expression in the adult mouse.

Topographic connection between corresponding compartments of the cerebellar cortex, cerebellar nuclei, and inferior olive form parallel modules, which are essential for the cerebellar function. Compared to the striped cortical compartmentalization which are labeled by molecular markers, such as aldolase C (Aldoc) or zebrin II, the presumed corresponding organization of the cerebellar nuclei and inferior olivary nucleus has not been much clarified. We focused on the expression pattern of pcdh10 gene coding cell adhesion molecule protocadherin 10 (Pcdh10) in adult mice. In the cortex, pcdh10 was strongly expressed in (a) Aldoc-positive vermal stripes a+//2+ in lobules VI-VII, (b) paravermal narrow stripes c+, d+, 4b+, 5a+ in crus I and neighboring lobules, and (c) paravermal stripes 4+//5+ across all lobules from lobule III to paraflocculus. In the cerebellar nuclei, pcdh10 was expressed strongly in the caudal part of the medial nucleus and the lateral part of the posterior interposed nucleus which project less to the medulla or to the red nucleus than to other metencephalic, mesencephalic, and diencephalic areas. In the inferior olive, pcdh10 was expressed strongly in the rostral and medioventrocaudal parts of the medial accessory olive which has connection with the mesencephalic areas rather than the spinal cord. Olivocerebellar and corticonuclear axonal labeling confirmed that the three cortical pcdh10-positive areas were topographically connected to the nuclear and olivary pcdh10-positive areas, demonstrating their coincidence with modular structures in the olivo-cortico-nuclear loop. We speculate that some of these modules are functionally involved in various nonsomatosensorimotor tasks via their afferent and efferent connections.

Malaria infection, poor nutrition and indoor air pollution mediate socioeconomic differences in adverse pregnancy outcomes in Cape Coast, Ghana.

BACKGROUND: The epidemiological evidence linking socioeconomic deprivation with adverse pregnancy outcomes has been conflicting mainly due to poor measurement of socioeconomic status (SES). Studies have also failed to evaluate the plausible pathways through which socioeconomic disadvantage impacts on pregnancy outcomes. We investigated the importance of maternal SES as determinant of birth weight and gestational duration in an urban area and evaluated main causal pathways for the influence of SES. METHODS: A population-based cross-sectional study was conducted among 559 mothers accessing postnatal services at the four main health facilities in Cape Coast, Ghana in 2011. Information on socioeconomic characteristics of the mothers was collected in a structured questionnaire. RESULTS: In multivariate linear regression adjusting for maternal age, parity and gender of newborn, low SES resulted in 292 g (95% CI: 440-145) reduction in birth weight. Important SES-related determinants were neighborhood poverty (221 g; 95% CI: 355-87), low education (187 g; 95% CI: 355-20), studentship during pregnancy (291 g; 95% CI: 506-76) and low income (147 g; 95% CI: 277-17). In causal pathway analysis, malaria infection (6-20%), poor nutrition (2-51%) and indoor air pollution (10-62%) mediated substantial proportions of the observed effects of socioeconomic deprivation on birth weight. Generalized linear models adjusting for confounders indicated a 218% (RR: 3.18; 95% CI: 1.41-7.21) risk increase of LBW and 83% (RR: 1.83; 95% CI: 1.31-2.56) of PTB among low income mothers. Low and middle SES was associated with 357% (RR: 4.57; 95% CI: 1.67-12.49) and 278% (RR: 3.78; 95% CI: 1.39-10.27) increased risk of LBW respectively. Malaria infection, poor nutrition and indoor air pollution respectively mediated 10-21%, 16-44% and 31-52% of the observed effects of socioeconomic disadvantage on LBW risk. CONCLUSION: We provide evidence of the effects of socioeconomic deprivation, substantially mediated by malaria infection, poor nutrition and indoor air pollution, on pregnancy outcomes in a developing country setting.