James A. Bourne

Compartmentalization of Cerebral Cortical Germinal Zones in a Lissencephalic Primate and Gyrencephalic Rodent

Previous studies of macaque and human cortices identified cytoarchitectonically distinct germinal zones; the ventricular zone inner subventricular zone (ISVZ), and outer subventricular zone (OSVZ). To date, the OSVZ has only been described in gyrencephalic brains, separated from the ISVZ by an inner fiber layer and considered a milestone that triggered increased neocortical neurogenesis. However, this observation has only been assessed in a handful of species without the identification of the different progenitor populations. We examined the Amazonian rodent agouti (Dasyprocta agouti) and the marmoset monkey (Callithrix jacchus) to further understand relationships among progenitor compartmentalization, proportions of various cortical progenitors, and degree of cortical folding. We identified a similar cytoarchitectonic distinction between the OSVZ and ISVZ at midgestation in both species. In the marmoset, we quantified the ventricular and abventricular divisions and observed similar proportions as previously described for the human and ferret brains. The proportions of radial glia, intermediate progenitors, and outer radial glial cell (oRG) populations were similar in midgestation lissencephalic marmoset as in gyrencephalic human or ferret. Our findings suggest that cytoarchitectonic subdivisions of SVZ are an evolutionary trend and not a primate specific feature, and a large population of oRG can be seen regardless of cortical folding.

Intracerebral microdialysis: 30 years as a tool for the neuroscientist

1. Microdialysis is an established technique for studying physiological, pharmacological and pathological changes of a wide range of low molecular weight substances in the brain extracellular fluid. Many studies have proven its sensitivity in sampling the extracellular space in discrete brain locations, such as the striatum, and monitoring the action of exogenous substances.

Connections of the Dorsomedial Visual Area: Pathways for Early Integration of Dorsal and Ventral Streams in Extrastriate Cortex

The dorsomedial area (DM), a subdivision of extrastriate cortex characterized by heavy myelination and relative emphasis on peripheral vision, remains the least understood of the main targets of striate cortex (V1) projections in primates. Here we placed retrograde tracer injections encompassing the full extent of this area in marmoset monkeys, and performed quantitative analyses of the numerical strengths and laminar patterns of its afferent connections. We found that feedforward projections from V1 and from the second visual area (V2) account for over half of the inputs to DM, and that the vast majority of the remaining connections come from other topographically organized visual cortices. Extrastriate projections to DM originate in approximately equal proportions from adjacent medial occipitoparietal areas, from the superior temporal motion-sensitive complex centered on the middle temporal area (MT), and from ventral stream-associated areas. Feedback from the posterior parietal cortex and other association areas accounts for <10% of the connections. These results do not support the hypothesis that DM is specifically associated with a medial subcircuit of the dorsal stream, important for visuomotor integration. Instead, they suggest an early-stage visual-processing node capable of contributing across cortical streams, much as V1 and V2 do. Thus, although DM may be important for providing visual inputs for guided body movements (which often depend on information contained in peripheral vision), this area is also likely to participate in other functions that require integration across wide expanses of visual space, such as perception of self-motion and contour completion.

Retinal afferents synapse with relay cells targeting the middle temporal area in the pulvinar and lateral geniculate nuclei.

Considerable debate continues regarding thalamic inputs to the middle temporal area (MT) of the visual cortex that bypass the primary visual cortex (V1) and the role they might have in the residual visual capability following a lesion of V1. Two specific retinothalamic projections to area MT have been speculated to relay through the medial portion of the inferior pulvinar nucleus (PIm) and the koniocellular layers of the dorsal lateral geniculate nucleus (LGN). Although a number of studies have demonstrated retinal inputs to regions of the thalamus where relays to area MT have been observed, the relationship between the retinal terminals and area MT relay cells has not been established. Here we examined direct retino-recipient regions of the marmoset monkey (Callithrix jacchus) pulvinar nucleus and the LGN following binocular injections of anterograde tracer, as well as area MT relay cells in these nuclei by injection of retrograde tracer into area MT. Retinal afferents were shown to synapse with area MT relay cells as demonstrated by colocalization with the presynaptic vesicle membrane protein synaptophysin. We also established the presence of direct synapes of retinal afferents on area MT relay cells within the PIm, as well as the koniocellular K1 and K3 layers of the LGN, thereby corroborating the existence of two disynaptic pathways from the retina to area MT that bypass V1.

Resolving the organization of the New World monkey third visual complex: the dorsal extrastriate cortex of the marmoset (Callithrix jacchus).

We tested current hypotheses on the functional organization of the third visual complex, a particularly controversial region of the primate extrastriate cortex. In anatomical experiments, injections of retrograde tracers were placed in the dorsal cortex immediately rostral to the second visual area (V2) of New World monkeys (Callithrix jacchus), revealing the topography of interconnections between the “third tier” cortex and the primary visual area (V1). The data indicate the presence of a dorsomedial area (DM), which represents the entire upper and lower quadrants of the visual field, and which receives strong, topographically organized projections from the superficial layers of V1. The visuotopic organization and boundaries of DM were confirmed by electrophysiological recordings in the same animals and by architectural characteristics which were distinct from those found in ventral extrastriate cortex rostral to V2. There was no electrophysiological or histological evidence for a transitional area between V2 and DM. In particular, the central representation of the upper quadrant in DM was directly adjacent to the representation of the horizontal meridian that marks the rostral border of V2. The present results argue in favor of the hypothesis that the third visual complex in New World monkeys contains different areas in its dorsal and ventral components: area DM, near the dorsal midline, and a homolog of area 19 of other mammals, located more lateral and ventrally. The characteristics of DM suggest that it may correspond to visual area 6 (V6) of Old World monkeys. J. Comp. Neurol. 483:164–191, 2005.

Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory

People with Down syndrome (DS) exhibit abnormal brain structure. Alterations affecting neurotransmission and signalling pathways that govern brain function are also evident. A large number of genes are simultaneously expressed at abnormal levels in DS; therefore, it is a challenge to determine which gene(s) contribute to specific abnormalities, and then identify the key molecular pathways involved. We generated RCAN1-TG mice to study the consequences of RCAN1 over-expression and investigate the contribution of RCAN1 to the brain phenotype of DS. RCAN1-TG mice exhibit structural brain abnormalities in those areas affected in DS. The volume and number of neurons within the hippocampus is reduced and this correlates with a defect in adult neurogenesis. The density of dendritic spines on RCAN1-TG hippocampal pyramidal neurons is also reduced. Deficits in hippocampal-dependent learning and short- and long-term memory are accompanied by a failure to maintain long-term potentiation (LTP) in hippocampal slices. In response to LTP induction, we observed diminished calcium transients and decreased phosphorylation of CaMKII and ERK1/2-proteins that are essential for the maintenance of LTP and formation of memory. Our data strongly suggest that RCAN1 plays an important role in normal brain development and function and its up-regulation likely contributes to the neural deficits associated with DS.

The Early Maturation of Visual Cortical Area MT is Dependent on Input from the Retinorecipient Medial Portion of the Inferior Pulvinar

The hierarchical development of the primate visual cortex and associated streams remains somewhat of a mystery. While anatomical, physiological, and psychological studies have demonstrated the early maturation of the dorsal “where”/“how” or motion cortical stream, little is known about the circuitry responsible. The influence of the retinogeniculostriate pathway has been investigated, but little attention has been paid to the role of two more recently described disynaptic retinothalamic projections to the middle temporal (MT) area, an early maturing dorsal stream cortical field, and which bypass the primary visual cortex (V1). These pathways are via the koniocellular layers of the lateral geniculate nucleus (LGN) and the medial portion of the inferior pulvinar (PIm). Both have been demonstrated in the adult nonhuman primate, but their influence during the maturation of the visual cortex is unknown. We used a combination of neural tracing and immunohistochemistry to follow the development of LGN and PIm inputs to area MT in the marmoset monkey. Our results revealed that the early maturation of area MT is likely due to the disynaptic retinopulvinar input and not the retinogeniculate input or the direct projection from V1. Furthermore, from soon after birth to adulthood, there was a dynamic shift in the ratio of input from these three structures to area MT, with an increasing dominance of the direct V1 afference.

Distribution and morphology of cholinergic, putative catecholaminergic and serotonergic neurons in the brain of the Egyptian rousette flying fox, Rousettus aegyptiacus

Over the past decade much controversy has surrounded the hypothesis that the megachiroptera, or megabats, share unique neural characteristics with the primates. These observations, which include similarities in visual pathways, have suggested that the megabats are more closely related to the primates than to the other group of the Chiropteran order, the microbats, and suggests a diphyletic origin of the Chiroptera. To contribute data relevant to this debate, we used immunohistochemical techniques to reveal the architecture of the neuromodulatory systems of the Egyptian rousette (Rousettus aegypticus), an echolocating megabat. Our findings revealed many similarities in the nuclear parcellation of the cholinergic, putative catecholaminergic and serotonergic systems with that seen in other mammals including the microbat. However, there were 11 discrete nuclei forming part of these systems in the brain of the megabat studied that were not evident in an earlier study of a microbat. The occurrence of these nuclei align the megabat studied more closely with primates than any other mammalian group and clearly distinguishes them from the microbat, which aligns with the insectivores. The neural systems investigated are not related to such Chiropteran specializations as echolocation, flight, vision or olfaction. If neural characteristics are considered strong indicators of phylogenetic relationships, then the data of the current study strongly supports the diphyletic origin of Chiroptera and aligns the megabat most closely with primates in agreement with studies of other neural characters.

Unravelling the development of the visual cortex: implications for plasticity and repair.

The visual cortex comprises over 50 areas in the human, each with a specified role and distinct physiology, connectivity and cellular morphology. How these individual areas emerge during development still remains something of a mystery and, although much attention has been paid to the initial stages of the development of the visual cortex, especially its lamination, very little is known about the mechanisms responsible for the arealization and functional organization of this region of the brain. In recent years we have started to discover that it is the interplay of intrinsic (molecular) and extrinsic (afferent connections) cues that are responsible for the maturation of individual areas, and that there is a spatiotemporal sequence in the maturation of the primary visual cortex (striate cortex, V1) and the multiple extrastriate/association areas. Studies in both humans and non‐human primates have started to highlight the specific neural underpinnings responsible for the maturation of the visual cortex, and how experience‐dependent plasticity and perturbations to the visual system can impact upon its normal development. Furthermore, damage to specific nuclei of the visual cortex, such as the primary visual cortex (V1), is a common occurrence as a result of a stroke, neurotrauma, disease or hypoxia in both neonates and adults alike. However, the consequences of a focal injury differ between the immature and adult brain, with the immature brain demonstrating a higher level of functional resilience. With better techniques for examining specific molecular and connectional changes, we are now starting to uncover the mechanisms responsible for the increased neural plasticity that leads to significant recovery following injury during this early phase of life. Further advances in our understanding of postnatal development/maturation and plasticity observed during early life could offer new strategies to improve outcomes by recapitulating aspects of the developmental program in the adult brain.

Genetic modulation of TLR8 response following bacterial phagocytosis

Human Toll‐like receptors (TLRs) TLR7, TLR8, and TLR9 are important immune sensors of foreign nucleic acids encountered by phagocytes. Although there is growing evidence implicating TLR7 and TLR9 in the detection of intracellular pathogenic bacteria, characterization of such a role for TLR8 is currently lacking. A recent genetic study has correlated the presence of a TLR8 single nucleotide polymorphism (SNP) (rs3764880:A>G; p.Met1Val) with the development of active tuberculosis, suggesting a role for TLR8 in the detection of phagosomal bacteria. Here we provide the first direct evidence that TLR8 sensing is activated in human monocytic cells following Helicobacter pylori phagocytosis. In addition, we show that rs3764880 fine tunes translation of the two TLR8 main isoforms, without affecting protein function. Although we show that TLR8 variant 2 (TLR8v2) is the prevalent form of TLR8 contributing to TLR8 function, we also uncover a role for the TLR8 long isoform (TLR8v1) in the positive regulation of TLR8 function in CD16+CD14+ differentiated monocytes. Thus, TLR8 sensing can be activated following bacterial phagocytosis, and rs3764880 may play a role in the modulation of TLR8‐dependent microbicidal response of infected macrophages. Hum Mutat 31:1069–1079, 2010.