Topography of visual and somatosensory inputs to the pontine nuclei in zebra finches (Taeniopygia guttata).

Birds have a comprehensive network of sensorimotor projections extending from the forebrain and midbrain to the cerebellum via the pontine nuclei, but the organization of these circuits in the pons is not thoroughly described. Inputs to the pontine nuclei include two retinorecipient areas, nucleus lentiformis mesencephali (LM) and nucleus of the basal optic root (nBOR), which are important structures for analyzing optic flow. Other crucial regions for visuomotor control include the retinorecipient ventral lateral geniculate nucleus (GLv), and optic tectum (TeO). These visual areas, together with the somatosensory area of the anterior (rostral) Wulst, which is homologous to the primary somatosensory cortex in mammals, project to the medial and lateral pontine nuclei (PM, PL). In this study, we used injections of fluorescent tracers to study the organization of these visual and somatosensory inputs to the pontine nuclei in zebra finches. We found a topographic organization of inputs to PM and PL. The PM has a lateral subdivision that predominantly receives projections from the ipsilateral anterior Wulst. The medial PM receives bands of inputs from the ipsilateral GLv and the nucleus laminaris precommisulis, located medial to LM. We also found that the lateral PL receives a strong ipsilateral projection from TeO, while the medial PL and region between the PM and PL receive less prominent projections from nBOR, bilaterally. We discuss these results in the context of the organization of pontine inputs to the cerebellum and possible functional implications of diverse somato-motor and visuomotor inputs and parcellation in the pontine nuclei.

Long-term hypogonadism diminishes the neuroprotective effects of dietary genistein in young adult ovariectomized rats after transient focal ischemia.

Increasing age disproportionately increases the risk of stroke among women compared to men of similar age, especially after menopause. One of the reasons for this observation is a sharp drop in circulating estrogens. However, the timing of initiation of estrogen replacement after menopause is associated with mixed beneficial and detrimental effects, hence contributing to widespread mistrust of estrogen use. Agents including soy isoflavones are being assessed as viable alternatives to estrogen therapy. In this study, we hypothesized that the neuroprotective effects of genistein, a soy isoflavone are less sensitive to the length of hypogonadism in young adult ovariectomized rats following cerebral ischemia. We expected that long-term hypogonadism will worsen motor and cognitive function, increase post-stroke inflammation with no effect on the neuroprotection of genistein. We compared the effect of treatment with dietary genistein (GEN) on short-term (2 weeks) and long-term hypogonadism (12 weeks) in young adult ovariectomized Sprague-Dawley rats on sensorimotor function, cognition and inflammation after focal ischemia. Dorsal Silastic implant of 17ß-estradiol (E2) was used as a control for hormone therapy. Long-term hypogonadism stroked rats performed worse than the short-term hypogonadism stroked rats on the motor and cognitive function tests. GEN did not improve neurological assessment and motor learning after either short-term or long-term hypogonadism. GEN improved cognitive flexibility after short-term hypogonadism but not after the long-term. Both GEN and E2 reduced tissue loss after short-term hypogonadism and reduced GFAP expression at the contralateral side of ischemia after long-term hypogonadism. The length of hypogonadism may differentially influence the neuroprotective effects of both GEN and E2 on the motor and cognitive functions in young adult rats.

Loss of CX3CR1 augments neutrophil infiltration into cochlear tissues after acoustic overstimulation.

The cochlea, the sensory organ for hearing, has a protected immune environment, segregated from the systemic immune system by the blood-labyrinth barrier. Previous studies have revealed that acute acoustic injury causes the infiltration of circulating leukocytes into the cochlea. However, the molecular mechanisms controlling immune cell trafficking are poorly understood. Here, we report the role of CX3CR1 in regulating the entry of neutrophils into the cochlea after acoustic trauma. We employed B6.129P-Cx3cr1tm1Litt /J mice, a transgenic strain that lacks the gene, Cx3cr1, for coding the fractalkine receptor. Our results demonstrate that lack of Cx3cr1 results in the augmentation of neutrophil infiltration into cochlear tissues after exposure to an intense noise of 120 dB SPL for 1 hr. Neutrophil distribution in the cochlea is site specific, and the infiltration level is positively associated with noise intensity. Moreover, neutrophils are short lived and macrophage phagocytosis plays a role in neutrophil clearance, consistent with typical neutrophil dynamics in inflamed non-cochlear tissues. Importantly, our study reveals the potentiation of noise-induced hearing loss and sensory cell loss in Cx3cr1-/- mice. In wild-type control mice (Cx3cr1+/+ ) exposed to the same noise, we also found neutrophils. However, neutrophils were present primarily inside the microvessels of the cochlea, with only a few in the cochlear tissues. Collectively, our data implicate CX3CR1-mediated signaling in controlling neutrophil migration from the circulation into cochlear tissues and provide a better understanding of the impacts of neutrophils on cochlear responses to acoustic injury.

The beneficial role of the synthetic microneurotrophin BNN20 in a focal demyelination model.

BNN20, a C17-spiroepoxy derivative of the neurosteroid dehydroepiandrosterone, has been shown to exhibit strong neuroprotective properties but its role in glial populations has not been assessed. Our aim was to investigate the effect of BNN20 on glial populations by using in vitro and in vivo approaches, taking advantage of the well-established lysophosphatidylcholine (LPC)-induced focal demyelination mouse model. Our in vivo studies, performed in male mice, showed that BNN20 treatment leads to an increased number of mature oligodendrocytes (OLs) in this model. It diminishes astrocytic accumulation during the demyelination phase leading to a faster remyelination process, while it does not affect oligodendrocyte precursor cell recruitment or microglia/macrophage accumulation. Additionally, our in vitro studies showed that BNN20 acts directly to OLs and enhances their maturation even after they were treated with LPC. This beneficial effect of BNN20 is mediated, primarily, through the neurotrophin receptor TrkA. In addition, BNN20 reduces microglial activation and their transition to their pro-inflammatory state upon lipopolysaccharides stimulation in vitro. Taken together our results suggest that BNN20 could serve as an important molecule to develop blood-brain barrier-permeable synthetic agonists of neurotrophin receptors that could reduce inflammation, protect and increase the number of functional OLs by promoting their differentiation/maturation.

Orcokinin in the central complex of the locust Schistocerca gregaria: Identification of immunostained neurons and colocalization with other neuroactive substances.

The central complex is a group of highly interconnected neuropils in the insect brain. It is involved in the control of spatial orientation, based on external compass cues and various internal needs. The functional and neurochemical organization of the central complex has been studied in detail in the desert locust Schistocerca gregaria. In addition to classical neurotransmitters, immunocytochemistry has provided evidence for a major contribution of neuropeptides to neural signaling within the central complex. To complement these data, we have identified all orcokinin-immunoreactive neurons in the locust central complex and associated brain areas. About 50 bilateral pairs of neurons innervating all substructures of the central complex exhibit orcokinin immunoreactivity. Among these were about 20 columnar neurons, 33 bilateral pairs of tangential neurons of the central body, and seven pairs of tangential neurons of the protocerebral bridge. In silico transcript analysis suggests the presence of eight different orcokinin-A type peptides in the desert locust. Double label experiments showed that all orcokinin-immunostained tangential neurons of the lateral accessory lobe cluster were also immunoreactive for GABA and the GABA-synthesizing enzyme glutamic acid decarboxylase. Two types of tangential neurons of the upper division of the central body were, furthermore, also labeled with an antiserum against Dip-allatostatin I. No colocalization was found with serotonin immunostaining. The data provide additional insights into the neurochemical organization of the locust central complex and suggest that orcokinin-peptides of the orcokinin-A gene act as neuroactive substances at all stages of signal processing in this brain area.

A natural endocast of an early Miocene odontocete and its implications in cetacean brain evolution.

The natural endocast Museo di Geologia e Paleontologia of the Università degli Studi di Torino (MGPT)-PU 13873 is described and analyzed in order to interpret its taxonomic affinities and its potential significance on our understanding of cetacean brain evolution. The endocast is from the early Miocene of Piedmont (between ca. 19 and 16 million years ago), Northwestern Italy, and shows a number of plesiomorphic characters. These include: scarcely rounded cerebral hemispheres, cerebellum exposed in dorsal view with little superimposition by the cerebral hemispheres, short temporal lobe, and long sylvian fissure. The distance between the hypophysis and the rostral pons is particularly high, as it was determined by the calculus of the hypothalamus quotient, suggesting that the development of a deep interpeduncular fossa was not as advanced as in living odontocetes. The encephalization quotient (EQ) of MGPT-PU 13873 is ~1.81; therefore, this specimen shows an EQ in line with other fossil whales of the same geological age (early Miocene). Comparative analysis shows that there is a critical lack of data from the late Miocene and Pliocene that prevents us to fully understand the recent evolution of the EQ diversity in whales. Moreover, the past diversity of brain size and shape in mysticetes is virtually unknown. All these observations point to the need of additional efforts to uncover evolutionary patterns and processes on cetacean brain evolution.

Differential development of myelin in zebra finch song nuclei.

Songbirds learn vocalizations by hearing and practicing songs. As song develops, the tempo becomes faster and more precise. In the songbird brain, discrete nuclei form interconnected myelinated circuits that control song acquisition and production. The myelin sheath increases the speed of action potential propagation by insulating the axons of neurons and by reducing membrane capacitance. As the brain develops, myelin increases in density, but the time course of myelin development across discrete song nuclei has not been systematically studied in a quantitative fashion. We tested the hypothesis that myelination develops differentially across time and song nuclei. We examined myelin development in the brains of the zebra finch (Taeniopygia guttata) from chick at posthatch day (d) 8 to adult (up to 147 d) in five major song nuclei: HVC (proper name), robust nucleus of the arcopallium (RA), Area X, lateral magnocellular nucleus of the anterior nidopallium, and medial portion of the dorsolateral thalamic nucleus (DLM). All of these nuclei showed an increase in the density of myelination during development but at different rates and to different final degrees. Exponential curve fits revealed that DLM showed earlier myelination than other nuclei, and HVC showed the slowest myelination of song nuclei. Together, these data show differential maturation of myelination in different portions of the song system. Such differential maturation would be well placed to play a role in regulating the development of learned song.

Female reproductive state is associated with changes in distinct arginine vasotocin cell types in the preoptic area of Astatotilapia burtoni.

Nonapeptides play a crucial role in mediating reproduction, aggression, and parental care across taxa. In fishes, arginine vasotocin (AVT) expression is related to social and/or reproductive status in most male fishes studied to date, and is linked to territorial defense, paternal care, and courtship. Despite a plethora of studies examining AVT in male fishes, relatively little is known about how AVT expression varies with female reproductive state or its role in female social behaviors. We used multiple methods for examining the AVT system in female African cichlid fish Astatotilapia burtoni, including immunohistochemistry for AVT, in situ hybridization for avt-mRNA, and quantitative PCR. Ovulated and mouthbrooding females had similar numbers of parvocellular, magnocellular, and gigantocellular AVT cells in the preoptic area. However, ovulated females had larger magnocellular and gigantocellular cells compared to mouthbrooding females, and gigantocellular AVT cell size correlated with the number of days brooding, such that late-stage brooding females had larger AVT cells than mid-stage brooding females. In addition, we found that ventral hypothalamic cells were more prominent in females compared to males, and were larger in mouthbrooding compared to ovulated females, suggesting a role in maternal care. Together, these data indicate that AVT neurons change across the reproductive cycle in female fishes, similar to that seen in males. These data on females complement studies in male A. burtoni, providing a comprehensive picture of the regulation and potential function of different AVT cell types in reproduction and social behaviors in both sexes.

Variations on a theme: Morphological variation in the secondary eye visual pathway across the order of Araneae.

Spiders possess a wide array of sensory-driven behaviors and therefore provide rich models for studying evolutionary hypotheses about the relationship between brain morphology, sensory systems, and behavior. Despite this, only a handful of studies have examined brain variation across the order of Araneae. In this study, I present descriptions of the gross brain morphology for 19 families of spiders that vary in eye morphology. Spiders showed the most variation in the secondary eye visual pathway. Based on this variation, spiders could be categorized into four groups. Group 1 spiders had small, underdeveloped laminae, no medullae, and no mushroom bodies. Group 2 spiders had large laminae, no medullae and large mushroom bodies. Group 3 spiders had laminae and some evidence of reduced medullae and mushroom bodies. Group 4 spiders had the most complex systems, with large laminae, medullae formed from optical glomeruli, and robust mushroom bodies. Within groups, there was large variation in the shape and size of individual regions, indicating possible variation in neuronal organization. The possible evolutionary implications of the loss of a dedicated olfactory organ in spiders and its effects on the mushroom body are also discussed.

Gpr37l1/prosaposin receptor regulates Ptch1 trafficking, Shh production, and cell proliferation in cerebellar primary astrocytes.

Mammalian cerebellar astrocytes critically regulate the differentiation and maturation of neuronal Purkinje cells and granule precursors. The G protein-coupled receptor 37-like 1 (Gpr37l1) is expressed by Bergmann astrocytes and interacts with patched 1 (Ptch1) at peri-ciliary membranes. Cerebellar primary astrocyte cultures from wild-type and Gpr37l1 null mutant mouse pups were established and studied. Primary cilia were produced by cultures of both genotypes, as well as Ptch1 and smoothened (Smo) components of the sonic hedgehog (Shh) mitogenic pathway. Compared to wild-type cells, Gpr37l1-/- astrocytes displayed striking increases in proliferative activity, Ptch1 protein expression and internalization, intracellular cholesterol content, ciliary localization of Smo, as well as a marked production of active Shh. Similar effects were reproduced by treating wild-type astrocytes with a putative prosaptide ligand of Gpr37l1. These findings indicate that Gpr37l1-Ptch1 interactions specifically regulate Ptch1 internalization and trafficking, with consequent stimulation of Shh production and activation of proliferative signaling.

Role of ß3-adrenergic receptor in the modulation of synaptic transmission and plasticity in mouse cerebellar cortex.

Convergent lines of evidence have recently highlighted ß3-adrenoreceptors (ARs) as a potentially critical target in the regulation of nervous and behavioral functions, including memory consolidation, anxiety, and depression. Nevertheless, the role of ß3-ARs in the cerebellum has been never investigated. To address this issue, we first examined the effects of pharmacological manipulation of ß3-ARs on motor learning in mice. We found that blockade of ß3-ARs by SR 59230A impaired the acquisition of the rotarod task with no effect on general locomotion. Since the parallel fiber-Purkinje cell (PF-PC) synapse is considered to be the main cerebellar locus of motor learning, we assessed ß3-AR modulatory action on this synapse as well as its expression in cerebellar slices. We demonstrate, for the first time, a strong expression of ß3-ARs on Purkinje cell soma and dendrites. In addition, whole-cell patch-clamp recordings revealed that bath application of ß3-AR agonist CL316,243 depressed the PF-PC excitatory postsynaptic currents via a postsynaptic mechanism mediated by the PI3K signaling pathway. Application of CL316,243 also interfered with the expression of PF long-term potentiation, whereas SR 59230A prevented the induction of LTD at PF-PC synapse. These results underline the critical role of ß3-AR on cerebellar synaptic transmission and plasticity and provide a new mechanism for adrenergic modulation of motor learning.

Ciliary melanin-concentrating hormone receptor 1 (MCHR1) is widely distributed in the murine CNS in a sex-independent manner.

Melanin-concentrating hormone (MCH) is a ubiquitous vertebrate neuropeptide predominantly synthesized by neurons of the diencephalon that can act through two G protein-coupled receptors, called MCHR1 and MCHR2. The expression of Mchr1 has been investigated in both rats and mice, but its synthesis remains poorly described. After identifying an antibody that detects MCHR1 with high specificity, we employed immunohistochemistry to map the distribution of MCHR1 in the CNS of rats and mice. Multiple neurochemical markers were also employed to characterize some of the neuronal populations that synthesize MCHR1. Our results show that MCHR1 is abundantly found in a subcellular structure called the primary cilium, which has been associated, among other functions, with the detection of free neurochemical messengers present in the extracellular space. Ciliary MCHR1 was found in a wide range of areas, including the olfactory bulb, cortical mantle, striatum, hippocampal formation, amygdala, midline thalamic nuclei, periventricular hypothalamic nuclei, midbrain areas, and in the spinal cord. No differences were observed between male and female mice, and interspecies differences were found in the caudate-putamen nucleus and the subgranular zone. Ciliary MCHR1 was found in close association with several neurochemical markers, including tyrosine hydroxylase, calretinin, kisspeptin, estrogen receptor, oxytocin, vasopressin, and corticotropin-releasing factor. Given the role of neuronal primary cilia in sensing free neurochemical messengers in the extracellular fluid, the widespread distribution of ciliary MCHR1, and the diverse neurochemical populations who synthesize MCHR1, our data indicate that nonsynaptic communication plays a prominent role in the normal function of the MCH system.

Retinal topography in two species of flamingo (Phoenicopteriformes: Phoenicopteridae).

In this study, we assessed eye morphology and retinal topography in two flamingo species, the Caribbean flamingo (Phoenicopterus ruber) and the Chilean flamingo (P. chilensis). Eye morphology is similar in both species and cornea size relative to eye size (C:A ratio) is intermediate between those previously reported for diurnal and nocturnal birds. Using stereology and retinal whole mounts, we estimate that the total number of Nissl-stained neurons in the retinal ganglion cell (RGC) layer in the Caribbean and Chilean flamingo is ~1.70 and 1.38 million, respectively. Both species have a well-defined visual streak with a peak neuron density of between 13,000 and 16,000 cells mm-2 located in a small central area. Neurons in the high-density regions are smaller and more homogeneous compared to those in medium- and low-density regions. Peak anatomical spatial resolving power in both species is approximately 10-11 cycles/deg. En-face images of the fundus in live Caribbean flamingos acquired using spectral domain optical coherence tomography (SD-OCT) revealed a thin, dark band running nasotemporally just dorsal to the pecten, which aligned with the visual streak in the retinal topography maps. Cross-sectional images (B-scans) obtained with SD-OCT showed that this dark band corresponds with an area of retinal thickening compared to adjacent areas. Neither the retinal whole mounts, nor the SD-OCT imaging revealed any evidence of a central fovea in either species. Overall, we suggest that eye morphology and retinal topography in flamingos reflects their cathemeral activity pattern and the physical nature of the habitats in which they live.

Postnatal development of the entorhinal cortex: A stereological study in macaque monkeys.

The entorhinal cortex is the main gateway for interactions between the neocortex and the hippocampus. Distinct regions, layers, and cells of the hippocampal formation exhibit different profiles of structural and molecular maturation during postnatal development. Here, we provide estimates of neuron number, neuronal soma size, and volume of the different layers and subdivisions of the monkey entorhinal cortex (Eo, Er, Elr, Ei, Elc, Ec, Ecl) during postnatal development. We found different developmental changes in neuronal soma size and volume of distinct layers in different subdivisions, but no changes in neuron number. Layers I and II developed early in most subdivisions. Layer III exhibited early maturation in Ec and Ecl, a two-step/early maturation in Ei and a late maturation in Er. Layers V and VI exhibited an early maturation in Ec and Ecl, a two-step and early maturation in Ei, and a late maturation in Er. Neuronal soma size increased transiently at 6 months of age and decreased thereafter to reach adult size, except in Layer II of Ei, and Layers II and III of Ec and Ecl. These findings support the theory that different hippocampal circuits exhibit distinct developmental profiles, which may subserve the emergence of different hippocampus-dependent memory processes. We discuss how the early maturation of the caudal entorhinal cortex may contribute to path integration and basic allocentric spatial processing, whereas the late maturation of the rostral entorhinal cortex may contribute to the increased precision of allocentric spatial representations and the temporal integration of individual items into episodic memories.

Distribution of aromatase in the brain of the African cichlid fish Astatotilapia burtoni: Aromatase expression, but not estrogen receptors, varies with female reproductive-state.

Estrogen synthesis and signaling in the brains of vertebrates has pleotropic effects ranging from neurogenesis to modulation of behaviors. The majority of studies on brain-derived estrogens focus on males, but estrogenic signaling in females likely plays important roles in regulation of reproductive cycling and social behaviors. We used females of the mouth brooding African cichlid fish, Astatotilapia burtoni, to test for reproductive state-dependent changes in estrogenic signaling capacity within microdissected brain nuclei that are important for social behaviors. Expression levels of the rate-limiting enzyme aromatase, but not estrogen receptors, measured by qPCR changes across the reproductive cycle. Gravid females that are close to spawning had higher aromatase levels in all brain regions compared to females with lower reproductive potential. This brain aromatase expression was positively correlated with circulating estradiol levels and ovarian readiness. Using chromogenic in situ hybridization we localized aromatase-expressing cells to ependymal regions bordering the ventricles from the forebrain to the hindbrain, and observed more abundant staining in gravid compared to mouth brooding females in most regions. Staining was most prominent in subpallial telencephalic regions, and diencephalic regions of the preoptic area, thalamus, and hypothalamus, but was also observed in sensory and sensorimotor areas of the midbrain and hindbrain. Aromatase expression was observed in radial glial cells, revealed by co-localization with the glial marker GFAP and absence of co-localization with the neuronal marker HuC/D. Collectively these results support the idea that brain-derived estradiol in females may serve important functions in reproductive state-dependent physiological and behavioral processes across vertebrates.

Sexual dimorphic distribution of cannabinoid 1 receptor mRNA in adult C57BL/6J mice.

The cannabinoid 1 receptor (CB1 R) is the most abundant G protein-coupled receptor in the brain and plays crucial roles in emotion and behavior by modulating or mediating synaptic transmission and plasticity. Differences in CB1 R density between male and female rodents may be associated with distinct behavioral phenotypes. In the rat brain, CB1 R expression is significantly lower in the prefrontal cortex and amygdala of estrus females than in males. However, differences in CB1 R distribution due to sex over the whole mouse brain are still largely unknown. Here, we systemically investigated the expression of CB1 R mRNA in the brains of both male and female adult C57BL/6J mice using fluorescence in situ hybridization. There were significantly more CB1 R positive cells in males than in females in the orbital cortex, insular cortex, cingulate cortex, piriform cortex, secondary visual cortex, caudate putamen (striatum), and ventral hippocampal CA1. There were significantly more CB1 R mRNA cells in females than males in the fornix and dorsal hypothalamus. However, in some regions, strong hybridization signals without sex differences were detected, such as in the motor cortex, septum, medial habenular nucleus, and inferior colliculus. Moreover, female mice displayed different CB1 R mRNA expression patterns in the medial amygdala, basolateral amygdala, and parabrachial nucleus during different phases of the estrous cycle. These findings provide a basis for understanding sexual dimorphism in physiological and pathological brain functions related to CB1 R.

Cross-modal modulation of cell activity by sound in first-order visual thalamic nucleus.

Cross-modal auditory influence on cell activity in the primary visual cortex emerging at short latencies raises the possibility that the first-order visual thalamic nucleus, which is considered dedicated to unimodal visual processing, could contribute to cross-modal sensory processing, as has been indicated in the auditory and somatosensory systems. To test this hypothesis, the effects of sound stimulation on visual cell activity in the dorsal lateral geniculate nucleus were examined in anesthetized rats, using juxta-cellular recording and labeling techniques. Visual responses evoked by light (white LED) were modulated by sound (noise burst) given simultaneously or 50-400 ms after the light, even though sound stimuli alone did not evoke cell activity. Alterations of visual response were observed in 71% of cells (57/80) with regard to response magnitude, latency, and/or burst spiking. Suppression predominated in response magnitude modulation, but de novo responses were also induced by combined stimulation. Sound affected not only onset responses but also late responses. Late responses were modulated by sound given before or after onset responses. Further, visual responses evoked by the second light stimulation of a double flash with a 150-700 ms interval were also modulated by sound given together with the first light stimulation. In morphological analysis of labeled cells projection cells comparable to X-, Y-, and W-like cells and interneurons were all susceptible to auditory influence. These findings suggest that the first-order visual thalamic nucleus incorporates auditory influence into parallel and complex thalamic visual processing for cross-modal modulation of visual attention and perception.

Pou3f4-expressing otic mesenchyme cells promote spiral ganglion neuron survival in the postnatal mouse cochlea.

During inner ear development, primary auditory neurons named spiral ganglion neurons (SGNs) are surrounded by otic mesenchyme cells, which express the transcription factor Pou3f4. Mutations in Pou3f4 are associated with DFNX2, the most common form of X-linked deafness and typically include developmental malformations of the middle ear and inner ear. It is known that interactions between Pou3f4-expressing mesenchyme cells and SGNs are important for proper axon bundling during development. However, Pou3f4 continues to be expressed through later phases of development, and potential interactions between Pou3f4 and SGNs during this period had not been explored. To address this, we documented Pou3f4 protein expression in the early postnatal mouse cochlea and compared SGNs in Pou3f4 knockout mice and littermate controls. In Pou3f4y/- mice, SGN density begins to decline by the end of the first postnatal week, with approximately 25% of SGNs ultimately lost. This period of SGN loss in Pou3f4y/- cochleae coincides with significant elevations in SGN apoptosis. Interestingly, this period also coincides with the presence of a transient population of Pou3f4-expressing cells around and within the spiral ganglion. To determine if Pou3f4 is normally required for SGN peripheral axon extension into the sensory domain, we used a genetic sparse labeling approach to track SGNs and found no differences compared with controls. We also found that Pou3f4 loss did not lead to changes in the proportions of Type I SGN subtypes. Overall, these data suggest that otic mesenchyme cells may play a role in maintaining SGN populations during the early postnatal period.

Proteostasis network alteration in lysosomal storage disorders: Insights from the mouse model of Krabbe disease.

In Krabbe disease, a mutation in GALC gene causes widespread demyelination determining cell death by apoptosis, mainly in oligodendrocytes and Schwann cells. Less is known on the molecular mechanisms induced by this deficiency. Here, we report an impairment in protein synthesis and degradation and in proteasomal clearance with a potential accumulation of the misfolded proteins and induction of the endoplasmic reticulum stress in the brain of 6-day-old twitcher mice (TM) (model of Krabbe disease). In particular, an imbalance of the immunoproteasome function was highlighted, useful for shaping adaptive immune response by neurological cells. Moreover, our data show an involvement of cytoskeleton remodeling in Krabbe pathogenesis, with a lamin meshwork disaggregation in twitcher oligodendrocytes in 6-day-old TM. This study provides interesting protein targets and mechanistic insight on the early onset of Krabbe disease that may be promising options to be tested in combination with currently available therapies to rescue Krabbe phenotype.

Afferent connections of the thalamic nucleus reuniens in the mouse.

The nucleus reuniens (RE) is part of the midline thalamus and one of the major sources of thalamic inputs to the hippocampal formation and the medial prefrontal cortex. However, it not only sends strong efferents to these areas but is also heavily innervated by both brain regions. Based on its connectivity and supported by functional studies the RE has been suggested to represent a major hub in reciprocal hippocampal-prefrontal communication. Indeed, inactivation studies have demonstrated that this nucleus is particularly important for cognitive behaviors which depend on prefrontal-hippocampal communication, such as working memory or memory consolidation. However, besides its central role in mediating hippocampal-prefrontal communication, the RE is target of a multitude of other cortical and subcortical afferents, which likely modulate its function. So far, however, studies that have systematically investigated the afferents of the RE have only been performed in rats. Because of the unique role of the mouse as a genetically accessible model system for mammalian brain circuit analysis we have mapped the afferent connectivity of the mouse RE using retrograde Fluoro-Gold tracing. Comparison with similar data from rats indicated a very high level of similarity in prefrontal and hippocampal afferents but some differences in afferent connectivity with other brain regions. In particular, our results suggest interspecies differences regarding the integration of the RE in circuits of fear, aversion, and defense.