Brain Structure and Function

Mitral cell development in the olfactory bulb of sharks: evidences of a conserved pattern of glutamatergic neurogenesis Abstract In mammals, the development of the olfactory bulb (OB) relies in part on the expression of transcription factors involved in the specifications/differentiation of glutamatergic cells. In a previous study from our group, a high molecular similarity was reported between mammals and cartilaginous fishes regarding the neurogenic mechanisms underlying the development of glutamatergic cells in the telencephalon. However, information about the transcriptional program operating in the development of the glutamatergic system (mainly represented by mitral cells) in the OB is lacking in the catshark Scyliorhinus canicula, a cartilaginous fish. Using immunohistochemistry and in situ hybridization techniques, we have found that, previously to the appearance of the olfactory primordium (OP), proliferating cells expressing Pax6 with molecular hallmarks of progenitor radial glia were located in the ventrolateral pallial ventricular zone. Later in development, when the OP is recognizable, a stream of Pax6-positive cells were observed between the ventricular zone and the OP, where transcription factors involved in mitral cell development in mammals (ScTbr2, ScNeuroD, Tbr1) are expressed. Later in development, these transcription factors became expressed in a layered-like structure where ScVglut1, a marker of mitral cells, is also present. Our data suggest that the transcriptional program related with the specification/differentiation of glutamatergic cells in the telencephalon has been conserved throughout the evolution of vertebrates. These results, in combination with previous studies concerning GABAergic neurogenesis in sharks, have evidenced that the OB of mammals and sharks shares similarities in the timing and molecular programs of development.

Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal Abstract Despite evidence that morphine-related pathologies reflect adaptations in NAc glutamate signaling, substantial gaps in basic information remain. The current study examines the impact of non-contingent acute, repeated, and withdrawal-inducing morphine dosing regimens on glutamate transmission in D1- or D2-MSNs in the nucleus accumbens shell (NAcSh) and core (NAcC) sub-regions in hopes of identifying excitatory plasticity that may contribute to unique facets of opioid addiction-related behavior. Following an acute morphine injection (10 mg/kg), average miniature excitatory postsynaptic current (mEPSC) amplitude mediated by AMPA-type glutamate receptors was increased at D1-MSNs in the both the NAcShl and NAcC, whereas only the frequency of events was elevated at D2-MSNs in the NAcSh. In contrast, spontaneous somatic withdrawal induced by escalating dose of repeated morphine twice per day (20, 40, 60, 80, 100 mg/kg) enhanced mEPSC frequency specifically at D2-MSNs in the NAcSh. Similar to previous findings, excitatory drive was elevated at NAcSh D1-MSNs after 10–14 days home cage abstinence. Following abstinence, an acute drug re-exposure produced a rapid and enduring endocytosis of GluA2-containing AMPARs at D1-MSNs in the shell, that when blocked by an intra-NAc shell infusion of the Tat-GluA23Y peptide, increased reinstatement of morphine place preference—a phenomenon distinctly different than effects previously found with cocaine. The present study is the first to directly identify unique circuit specific adaptations in NAc glutamate synaptic transmission associated with morphine-related acute reward and somatic withdrawal as well as post-abstinence short-term plasticity. Moreover, while differing classes of abused drugs (i.e., psychostimulants and opioids) produce seemingly similar bidirectional plasticity in the NAc following drug re-exposure, our findings indicate this plasticity has distinct behavioral consequences.

White matter asymmetries in human situs inversus totalis Abstract Diffusion weighted imaging (DWI) was used to investigate white matter asymmetries in participants with situs inversus totalis (SIT) and matched controls. Regardless of visceral condition, hemispheric differences were found for the arcuate fasciculus (ARC) and the superior longitudinal fasciculus (SLF), which are involved in language and visuospatial functioning, respectively. The ARC appears lateralized to the left hemisphere, analogous to the left lateralization of functional areas associated with language. The SLF, on the other hand, is lateralized to the right, corresponding with rightward lateralization of visuospatial functioning. Interestingly, SIT participants show a significantly lower number of streamlines in the Uncinate Fasciculus (UNC). In addition, UNC volume appears associated with measures of cognitive performance, a finding in line with previously reported performance differences between SIT participants and controls.

The differential impact of acute microglia activation on the excitability of cholinergic neurons in the mouse medial septum Abstract The medial septal nucleus is one of the basal forebrain nuclei that projects cholinergic input to the hippocampus and cortex. Two of the hallmarks of Alzheimer’s disease (AD) are a significant loss of cholinergic transmission and neuroinflammation, and it has been suggested that these two hallmarks are causally linked to the medial septum. Therefore, we have investigated the age-related susceptibility of medial septal cholinergic neurons to glial activation, mediated via peripheral administration of lipopolysaccharide (500 μg/kg) into ChAT(BAC)-eGFP mice at different ages (3–22 months). Our results show that during normal aging, cholinergic neurons experience a bi-phasic excitability profile, in which increased excitability at adulthood (ages ranging between 9 and 12 months) decreases in aged animals (> 18 months). Moreover, activation of glia had a differential impact on mice from different age groups, affecting K+ conductances in young and adult animals, without affecting aged mice. These findings provide a potential explanation for the increased vulnerability of cholinergic neurons to neuroinflammation with aging as reported previously, thus providing a link to the impact of acute neuroinflammation in AD.

On the existence of mechanoreceptors within the neurovascular unit of the mammalian brain Abstract We describe a set of perivascular interneurons (PINs) with series of fibro-vesicular complexes (FVCs) throughout the gray matter of the adult rabbit and rat brains. PIN–FVCs are ubiquitous throughout the brain vasculature as detected in Golgi-impregnated specimens. Most PINs are small, aspiny cells with short or long (> 1 mm) axons that split and travel along arterial blood vessels. Upon ramification, axons form FVCs around the arising vascular branches; then, paired axons run parallel to the vessel wall until another ramification ensues, and a new FVC is formed. Cytologically, FVCs consist of clusters of perivascular bulbs (PVBs) encircling the precapillary and capillary wall surrounded by end-feet and the extracellular matrix of endothelial cells and pericytes. A PVB contains mitochondria, multivesicular bodies, and granules with a membranous core, similar to Meissner corpuscles and other mechanoreceptors. Some PVBs form asymmetrical, axo-spinous synapses with presumptive adjacent neurons. PINs appear to correspond to the type 1 nNOS-positive neurons whose FVCs co-label with markers of sensory fiber-terminals surrounded by astrocytic end-feet. The PIN is conserved in adult cats and rhesus monkey specimens. The location, ubiquity throughout the vasculature of the mammalian brain, and cytological organization of the PIN–FVCs suggests that it is a sensory receptor intrinsic to the mammalian neurovascular unit that corresponds to an afferent limb of the sensorimotor feed-back mechanism controlling local blood flow.

A network approach to brain form, cortical topology and human evolution Abstract Network analysis provides a quantitative tool to investigate the topological properties of a system. In anatomy, it can be employed to investigate the spatial organization of body parts according to their contiguity and patterns of physical contact. In this study, we build a model representing the spatial adjacency of the major regions of the human brain often considered in evolutionary neuroanatomy, to analyse its topological features. Results suggest that the frontal lobe is topologically independent of the posterior regions of the brain, which in turn are more integrated and influenced by reciprocal constraints. The precentral gyrus represents a hinge between the anterior and posterior blocks. The lateral temporal cortex is particularly influenced by the neighbouring regions, while the parietal cortex is minimally constrained by the overall brain organization. Beyond the reciprocal spatial influences among cortical areas, brain form is further constrained by spatial and mechanical influence of the braincase, including bone and connective elements. The anterior fossa and the parietal bones are the elements more sensitive to the brain–braincase spatial organization. These topological properties must be properly considered when making inferences on evolutionary variations and macroscopic differences of the human brain morphology.

Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner Abstract The palmitoyl acyltransferase ZDHHC7 belongs to the DHHC family responsible for the covalent attachment of palmitic acid (palmitoylation) to target proteins. Among synaptic proteins, its main targets are sex steroid receptors such as the estrogen receptors. When palmitoylated, these couple to membrane microdomains and elicit non-genomic rapid responses. Such coupling is found particularly in cortico-limbic brain areas which impact structure, function, and behavioral outcomes. Thus far, the functional role of ZDHHC7 has not been investigated in this context. To directly analyze an impact of ZDHHC7 on brain anatomy, microstructure, connectivity, function, and behavior, we generated a mutant mouse in which the Zdhhc7 gene is constitutively inactivated. Male and female Zdhhc7−/− mice were phenotypically compared with wild-type mice using behavioral tests, electrophysiology, protein analyses, and neuroimaging with diffusion tensor-based fiber tractography. Zdhhc7-deficiency impaired excitatory transmission, synaptic plasticity at hippocampal Schaffer collateral CA1 synapses, and hippocampal structural connectivity in both sexes in similar manners. Effects on both sexes but in different manners appeared in medial prefrontal cortical synaptic transmission and in hippocampal microstructures. Finally, Zdhhc7-deficiency affected anxiety-related behaviors exclusively in females. Our data demonstrated the importance of Zdhhc7 for assembling proper brain structure, function, and behavior on a system level in mice in a sex-related manner. Given the prominent role of sex-specificity also in humans and associated mental disorders, Zdhhc7−/− mice might provide a promising model for in-depth investigation of potentially underlying sex-specifically altered mechanisms.

The neural correlates of auditory-verbal short-term memory: a voxel-based lesion-symptom mapping study on 103 patients after glioma removal Abstract The relationship between verbal-auditory short-term memory (STM) and language is an open area of debate and contrasting hypotheses have been proposed, suggesting either that STM would strongly rely on language-related processes, or that it depends on a dedicated system related to language, but independent from it. In this study we examined 103 patients undergoing surgery for glioma resection in the left or right hemisphere, and we conducted a VLSM analysis on their behavioral performance on auditory-verbal STM, as well as on more general verbal and nonverbal tasks. The aim was to investigate whether the anatomical correlates of auditory-verbal STM were part of the language system or they were spatially segregated from it. VLSM results showed that digit span scores were linked to lesions in both the left supramarginal gyrus and superior-posterior temporal areas, as reported in the literature on patients with a selective deficit of auditory-verbal STM. Conversely, other verbal tasks involved areas only partly overlapping with those found for digit span, with repetition being affected by lesions in more anterior regions in the parietal, temporal, and frontal lobes, and word comprehension by lesions in a network including cortical and subcortical pathways in the temporal lobe. The present results, thus, show that auditory-verbal STM neural correlates are only partially overlapping with those supporting comprehension and production: while the left posterior–superior temporal cortex, involved in speech perception, takes part in both functions, the left supramarginal gyrus has a consistent and specific role only in STM, supporting the hypothesis of interacting but segregated networks.

Connexin-36 distribution and layer-specific topography in the cat retina Abstract Connexin-36 (Cx36) is the major constituent of mammalian retinal gap junctions positioned in key signal pathways. Here, we examined the laminar and large-scale topographical distribution of Cx36 punctate immunolabels in the retina of the cat, a classical model of the mammalian visual system. Calretinin-immunoreactive (CaR-IR) cell populations served to outline the nuclear and plexiform layers and to stain specific neuronal populations. CaR-IR cells included horizontal cells in the outer retina, numerous amacrine cells, and scattered cells in the ganglion cell layer. Cx36-IR plaques were found among horizontal cell dendrites albeit without systematic colocalization of the two labels. Diffuse Cx36 immunoreactivity was found in the cytoplasm of AII amacrine cells, but no colocalization of Cx36 plaques was observed with either the perikarya or the long varicose dendrites of the CaR-IR non-AII amacrine cells. Cx36 puncta were seen throughout the entire inner plexiform layer showing their highest density in the ON sublamina. The densities of AII amacrine cell bodies and Cx36 plaques in the ON sublamina were strongly correlated across a wide range of eccentricities suggesting their anatomical association. However, the high number of plaques per AII cell suggests that a considerable fraction of Cx36 gap junctions in the ON sublamina is formed by other cell types than AII amacrine cells drawing attention to extensive but less studied electrically coupled networks.

Localization, distribution and expression of growth hormone in the brain of Asian Catfish, Clarias batrachus Abstract Intense immunoreactivity was observed in several neurons of the nucleus preopticus (NPO) located in the preoptic area (POA), in addition to several GH cells in the proximal pars distalis (PPD) of the pituitary gland of Clarias batrachus. The immunoreactive cells were located in the paraventricular as well as supraoptic subdivisions of the NPO. GH immunoreactive fibers projecting from the neurons were traced caudally to the pituitary gland via the conspicuous preoptico-hypophysial tract (PHT) in the ventral tuberal area to the neurohypophysis of the pituitary. Apart from these immunoreactive fibers in the preoptico-hypophysial tract, some fine caliber fiber probably arising from the neurons located dorsally in the NPO also showed GH immunoreactivity, and these fibers constituted an independent tract. Bilaterally, it extended caudally through the dorsal hypothalamus almost as far as the saccus vasculosus where it curved sharply to descend into the caudal tuberal region and finally entered into the pituitary gland. The fibers of this tract were mainly distributed in the rostral pars distalis (RPD). This tract is quite distinct from the preoptico-hypophysial tract and herein called as the accessory preoptico-hypophysial tract (APHT). Expression of GH mRNA in the NPO was found 65-fold more than that of the control region, rostral cerebellum. These results altogether suggest that GH secreted by NPO neurons might serve as a neuro-modulatory role in the brain of C. batrachus. Transportation of GH to the pituitary via two independent tracts may represent the duality of neuroendocrine function. The present study underscores the possibility that GH in the brain of vertebrates may be a phylogenetically conserved phenomenon and provide clues to our understanding of the evolutionary course taken by the hormone.