Calcium-binding Proteins Parvalbumin Research Articles

Calcium currents in striatal fast-spiking interneurons: dopaminergic modulation of CaV1 channels

BackgroundStriatal fast-spiking interneurons (FSI) are a subset of GABAergic cells that express calcium-binding protein parvalbumin (PV). They provide feed-forward inhibition to striatal projection neurons (SPNs), receive cortical, thalamic and dopaminergic inputs and are coupled together by electrical and chemical synapses, being important components of the striatal circuitry. It is known that dopamine (DA) depolarizes FSI via D1-class DA receptors, but no studies about the ionic mechanism of this action have been reported. Here we ask about the ion channels that are the effectors of DA actions. This work studies their Ca2+ currents.ResultsWhole-cell recordings in acutely dissociated and identified FSI from PV-Cre transgenic mice were used to show that FSI express an array of voltage gated Ca2+ channel classes: CaV1, CaV2.1, CaV2.2, CaV2.3 and CaV3. However, CaV1 Ca2+ channel carries most of the whole-cell Ca2+ current in FSI. Activation of D1-like class of DA receptors by the D1-receptor selective agonist SKF-81297 (SKF) enhances whole-cell Ca2+ currents through CaV1 channels modulation. A previous block of CaV1 channels with nicardipine occludes the action of the DA-agonist, suggesting that no other Ca2+ channel is modulated by D1-receptor activation. Bath application of SKF in brain slices increases the firing rate and activity of FSI as measured with both whole-cell and Ca2+ imaging recordings. These actions are reduced by nicardipine.ConclusionsThe present work discloses one final effector of DA modulation in FSI. We conclude that the facilitatory action of DA in FSI is in part due to CaV1 Ca2+ channels positive modulation.

Electrophysiological properties and projections of lateral hypothalamic parvalbumin positive neurons.

Cracking the cytoarchitectural organization, activity patterns, and neurotransmitter nature of genetically-distinct cell types in the lateral hypothalamus (LH) is fundamental to develop a mechanistic understanding of how activity dynamics within this brain region are generated and operate together through synaptic connections to regulate circuit function. However, the precise mechanisms through which LH circuits orchestrate such dynamics have remained elusive due to the heterogeneity of the intermingled and functionally distinct cell types in this brain region. Here we reveal that a cell type in the mouse LH identified by the expression of the calcium-binding protein parvalbumin (PVALB; LHPV) is fast-spiking, releases the excitatory neurotransmitter glutamate, and sends long range projections throughout the brain. Thus, our findings challenge long-standing concepts that define neurons with a fast-spiking phenotype as exclusively GABAergic. Furthermore, we provide for the first time a detailed characterization of the electrophysiological properties of these neurons. Our work identifies LHPV neurons as a novel functional component within the LH glutamatergic circuitry.

Improving the Application of High Molecular Weight Biotinylated Dextran Amine for Thalamocortical Projection Tracing in the Rat

High molecular weight biotinylated dextran amine (BDA) has been used as a highly sensitive neuroanatomical tracer for many decades. Since the quality of its labeling was affected by various factors, here, we provide a refined protocol for the application of high molecular weight BDA for studying optimal neural labeling in the central nervous system. After stereotactic injection of BDA into the ventral posteromedial nucleus (VPM) of the thalamus in the rat through a delicate glass pipette, BDA was stained with fluorescent streptavidin-Alexa (AF) 594 and counterstained with fluorescent Nissl stain AF500/525. On the background of green Nissl staining, the red BDA labeling, including neuronal cell bodies and axonal terminals, was more distinctly demonstrated in the somatosensory cortex. Furthermore, double fluorescent staining for BDA and the calcium-binding protein parvalbumin (PV) was carried out to observe the correlation of BDA labeling and PV-positive interneurons in the cortical target, providing the opportunity to study the local neural circuits and their chemical characteristics. Thus, this refined method is not only suitable for visualizing high quality neural labeling with the high molecular weight BDA through reciprocal neural pathways between the thalamus and cerebral cortex, but also will permit the simultaneous demonstration of other neural markers with fluorescent histochemistry or immunochemistry.

Improving the Application of High Molecular Weight Biotinylated Dextran Amine for Thalamocortical Projection Tracing in the Rat.

High molecular weight biotinylated dextran amine (BDA) has been used as a highly sensitive neuroanatomical tracer for many decades. Since the quality of its labeling was affected by various factors, here, we provide a refined protocol for the application of high molecular weight BDA for studying optimal neural labeling in the central nervous system. After stereotactic injection of BDA into the ventral posteromedial nucleus (VPM) of the thalamus in the rat through a delicate glass pipette, BDA was stained with fluorescent streptavidin-Alexa (AF) 594 and counterstained with fluorescent Nissl stain AF500/525. On the background of green Nissl staining, the red BDA labeling, including neuronal cell bodies and axonal terminals, was more distinctly demonstrated in the somatosensory cortex. Furthermore, double fluorescent staining for BDA and the calcium-binding protein parvalbumin (PV) was carried out to observe the correlation of BDA labeling and PV-positive interneurons in the cortical target, providing the opportunity to study the local neural circuits and their chemical characteristics. Thus, this refined method is not only suitable for visualizing high quality neural labeling with the high molecular weight BDA through reciprocal neural pathways between the thalamus and cerebral cortex, but also will permit the simultaneous demonstration of other neural markers with fluorescent histochemistry or immunochemistry.

17-\u03b2 estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms

BackgroundAutism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by two core symptoms: impaired social interaction and communication, and restricted, repetitive behaviors and interests. The pathophysiology of ASD is not yet fully understood, due to a plethora of genetic and environmental risk factors that might be associated with or causal for ASD. Recent findings suggest that one putative convergent pathway for some forms of ASD might be the downregulation of the calcium-binding protein parvalbumin (PV). PV-deficient mice (PV−/−, PV+/−), as well as Shank1−/−, Shank3−/−, and VPA mice, which show behavioral deficits relevant to all human ASD core symptoms, are all characterized by lower PV expression levels.MethodsBased on the hypothesis that PV expression might be increased by 17-β estradiol (E2), PV+/− mice were treated with E2 from postnatal days 5–15 and ASD-related behavior was tested between postnatal days 25 and 31.ResultsPV expression levels were significantly increased after E2 treatment and, concomitantly, sociability deficits in PV+/− mice in the direct reciprocal social interaction and the 3-chamber social approach assay, as well as repetitive behaviors, were attenuated. E2 treatment of PV+/+ mice did not increase PV levels and had detrimental effects on sociability and repetitive behavior. In PV−/− mice, E2 obviously did not affect PV levels; tested behaviors were not different from the ones in vehicle-treated PV−/− mice.ConclusionOur results suggest that the E2-linked amelioration of ASD-like behaviors is specifically occurring in PV+/− mice, indicating that PV upregulation is required for the E2-mediated rescue of ASD-relevant behavioral impairments.

Enucleation Induces Parvalbumin and Glial Fibrillary Acidic Protein, but Not Calbindin D28k Protein Expression in Superior Colliculus of Wistar Rats

Background: It is known that eye enucleation causes various morphological and functional alterations in the central nervous system (CNS). The purpose of this study was to examine the sub-chronic effects of monocular enucleation on the distribution of the calcium binding proteins calbindin D28k (CB) and parvalbumin (PV) as well as the glial fibrillary acidic protein (GFAP) immunoreactivity in the superior colliculus (SC) of Wistar rats.Materials and Methods: Thirty young adult (8 weeks) male Wistar rats from SLC (Shizuoka, Japan), weighing 200-250 grams, were housed in separate cages under controlled conditions with a constant temperature kept in 12:12 light/dark cycle and ad libitum water and food. In this study the rats were divided into two groups, a control and an enucleated groups. The experimental group received unilateral eye enucleation and was allowed 1, 4 or 12 weeks recovery before sacrificed.Results: Unilateral enucleation over a period of 1 week or more caused a decrease in the number CB-immunoreactive (CBIR) neurons. This loss was associated with an increase in GFAP-IR astrocytes in the superficial gray layer and the optic layer of the SC with contralateral side predominance. In addition, the CB-IR neurons illustrated a smaller soma and poor dendritic arborization. Conversely, the GFAP-IR astrocytes were hypertrophied with longer foot processes on the contralateral side of enucleation. Interestingly, the number of PV-IR neurons was elevated for up to 4 weeks in enucleated rats versus shamoperated rats.Conclusion: This study demonstrates the importance of calcium-binding protein homeostasis and reversible glial response for maintaining variability of neuronal function in sub-cortical visual centers following optic nerve deafferentation.Keywords: enucleation, superior colliculus, calbindin D28k, parvalbumin, glial fibrillary acidic protein

Chapter 25 - Mapping pathologic circuitry in schizophrenia

Schizophrenia is a complex disorder lacking an effective treatment option for the pervasive and debilitating cognitive impairments experienced by patients. Working memory is a core cognitive function impaired in schizophrenia that depends upon activation of distributed neural network, including the circuitry of the dorsolateral prefrontal cortex (DLPFC). Accordingly, individuals diagnosed with schizophrenia show reduced DLPFC activation while performing working-memory tasks. This lower DLPFC activation appears to be an integral part of the disease pathophysiology, and not simply a reflection of poor performance. Thus, the cellular and circuitry alterations that underlie lower DLPFC neuronal activity in schizophrenia must be determined in order to identify appropriate therapeutic targets. Studies using human postmortem brain tissue provide a robust way to investigate and characterize these cellular and circuitry alterations at multiple levels of resolution, and such studies provide essential information that cannot be obtained either through in vivo studies in humans or through experimental animal models. Studies examining neuronal morphology, protein expression and localization, and transcript levels indicate that a microcircuit composed of excitatory pyramidal cells and inhibitory interneurons containing the calcium-binding protein parvalbumin is altered in the DLPFC of subjects with schizophrenia and likely contributes to DLPFC dysfunction.

Characterization of calbindin D28k expressing interneurons in the ventral horn of the mouse spinal cord.

Expression of the calcium binding protein, calbindin (CB), is well established as a hallmark of Renshaw cells, a class of interneurons found in spatially restricted areas in the ventral spinal cord that directly modulate motor neuron activity. CB expression, however, is not restricted only to Renshaw cells in the ventral horn, and within this population other interneuron subtypes may be identifiable on the basis of cell position and the potential for coexpression of other calcium binding proteins. Here we have quantified the changing CB expression pattern in the ventral spinal cord across postnatal development in the mouse. Fewer neurons express CB as postnatal development progresses, and those neurons frequently coexpress other calcium binding proteins (calretinin and parvalbumin) in subpopulations with distinct spatial distributions. We also found a significant portion of CB-expressing interneurons receive putative synaptic contacts from primary sensory afferents. These findings suggest CB labels a heterogeneous group of interneurons in the ventral horn, some of which may process sensory information. Based on cellular position, CB expression may be a shared feature of subsets of interneurons arising from multiple ventral progenitor domains. Developmental Dynamics 247:185-193, 2018. © 2017 Wiley Periodicals, Inc.

Comparative Pulvinar Organization Across Different Primate Species.

In this chapter, we compare the pattern of pulvinar immunohistochemical staining for the calcium-binding proteins calbindin and parvalbumin and for the neurofilament protein SMI-32 in macaque, capuchin, and squirrel monkeys. This group of New and Old World primates shares five similar pulvinar subdivisions: PIP, PIM, PIC, PIL, and PILS. In the Old World macaque monkey, the inferior-lateral pulvinar can be subdivided into the P1 and P2 fields based on its connectivity with visual area V1. On the other hand, only the P1 field and no P2 was found in the New World capuchin monkey. Notably, the similarities in chemoarchitecture contrast with the distinct connectivity patterns and the different visuotopic organizations found across the species.

Developmental and adult characterization of secretagogin expressing amacrine cells in zebrafish retina.

Calcium binding proteins show stereotypical expression patterns within diverse neuron types across the central nervous system. Here, we provide a characterization of developmental and adult secretagogin-immunolabelled neurons in the zebrafish retina with an emphasis on co-expression of multiple calcium binding proteins. Secretagogin is a recently identified and cloned member of the F-hand family of calcium binding proteins, which labels distinct neuron populations in the retinas of mammalian vertebrates. Both the adult distribution of secretagogin labeled retinal neurons as well as the developmental expression indicative of the stage of neurogenesis during which this calcium binding protein is expressed was quantified. Secretagogin expression was confined to an amacrine interneuron population in the inner nuclear layer, with monostratified neurites in the center of the inner plexiform layer and a relatively regular soma distribution (regularity index > 2.5 across central–peripheral areas). However, only a subpopulation (~60%) co-labeled with gamma-aminobutyric acid as their neurotransmitter, suggesting that possibly two amacrine subtypes are secretagogin immunoreactive. Quantitative co-labeling analysis with other known amacrine subtype markers including the three main calcium binding proteins parvalbumin, calbindin and calretinin identifies secretagogin immunoreactive neurons as a distinct neuron population. The highest density of secretagogin cells of ~1800 cells / mm2 remained relatively evenly along the horizontal meridian, whilst the density dropped of to 125 cells / mm2 towards the dorsal and ventral periphery. Thus, secretagogin represents a new amacrine label within the zebrafish retina. The developmental expression suggests a possible role in late stage differentiation. This characterization forms the basis of functional studies assessing how the expression of distinct calcium binding proteins might be regulated to compensate for the loss of one of the others.

P 59 Interplay of the cellular actions of neuropeptide Y and transcranial magnetic theta-burst stimulation on cortical inhibitory systems – a rat study

Questions Our previous studies showed that intermittent theta-burst stimulation (iTBS) applied via transcranial magnetic stimulation (TMS) to the rat brain strongly reduced the expression of the calcium-binding protein parvalbumin (PV) in fast-spiking inhibitory interneurons (FSI). This finding indicates that disinhibition and the associated increase in cortical excitability may be one way to open a window for plastic changes in the cortical network. The mechanisms leading to reduced PV expression are not known but are either related to a strong activation during iTBS or a subsequent reduction in glutamatergic excitation of FSI in a manner of Ltd. One well-described regulator of glutamate release at excitatory terminals is neuropeptide Y (NPY) which has been shown to be up-regulated after epileptic activity. Therefore, we tested if iTBS increases the expression of NPY in rat cortex, whether the reduced PV expression in FSI is associated with reduced activity of excitatory inputs and finally if intrathecal application of NPY prior to TMS can counteract the cortical iTBS effect. Methods In a first study, parallel changes in the cortical expression of PV and NPY in rats previously treated with one to five blocks of iTBS (600 pulses per block, intervals of 15 min) were analysed using immunohistochemistry. In a second study, we analysed the relationship between the level of PV expression of single FSI and the strength of glutamatergic input measured as the level of expression of the vesicular glutamate transporter type 1 (VGluT1) in cortical synapses terminating on FSI. Finally in a third study, rats received either 20 μ l NPY (24 nMol) or methylene blue as a control (MB) via intracranial injection to the left lateral ventricle (2 μ l/min) followed 60 min later by either verum or sham iTBS (3 blocks @ 15 min = 1800 pulses) to test if enhanced NPY level can influence the effect of iTBS on PV and vGluT1 expression. Results In a dose-dependent fashion, iTBS gradually decreased the number of PV+ neurons but also increased the level of NPY in the neuropil and the number of NPY+ neurons. Interneurons showing low PV expression had a significantly weaker labelling of glutamatergic cortical input (less vGluT1) than cells showing high PV level. NPY injected into the lateral ventricle of the left forebrain (no diffusion to the right hemisphere) prevented the reduction of PV+ cells (−40%) by iTBS in the left but not in the right hemisphere and further increased the number of PV+ cells. A slight increase in PV+ cells was also evident in sham stimulated animals when comparing NPY with MB injections. Conclusions As expected, iTBS increased the expression of NPY likely due to the strong and highly synchronous activation of cortical networks. Since strong excitation is especially harmful to FSI, the reduction in PV expression appears to signal a post-stimulation depression of excitatory inputs and subsequent hypoactivity of these interneurons. The finding that NPY prevents the strong reduction in PV expression indicates that it is able to prevent over-excitation of FSI. This study has been supported a grant of the Federal Ministry of Education and Research (BMBF): GCBS-WP1_Bochum ( 01EE1403B ) to K. Funke.

The development of perineuronal nets around parvalbumin gabaergic neurons in the medial prefrontal cortex and basolateral amygdala of rats.

Perineuronal nets (PNNs) are extracellular matrix structures that preferentially surround mature GABAergic neurons that express the calcium-binding protein parvalbumin (PV). It has been suggested that aberrant PNN formation in humans may contribute to psychological disorders, many of which emerge during childhood and adolescence. The present experiment investigated the normative developmental trajectory of PNN formation in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) in juvenile (P24), adolescent (P35-36), and adult (∼P70) rats. Dual-immunofluorescence staining revealed that there was a marked increase in the number of PNNs in both the prelimbic and infralimbic regions of the mPFC across the transition from the juvenile to adolescent period. Although there were no differences in the number of PV neurons across age groups, adolescent and adult rats had more PNNs surrounding PV neurons than juveniles. In contrast to the mPFC, juvenile and adolescent rats had similar total numbers of PNNs in the BLA, and total numbers of PNNs were even higher in adults in this region. In the BLA, adults had more PNNs around non-PV cells whereas the number of PV cells with PNNs did not differ across ages. However, expression patterns differed within subregions of the BLA such that adults had the most PNNs around both PV and non-PV cells in the lateral nucleus, with no age differences observed in the basal nucleus. These findings demonstrate that the juvenile to adolescent developmental period is an important time for the formation of prefrontal PNNs and the maturation of PV inhibitory neurons. (PsycINFO Database Record

Ultrastructural analysis of parvalbumin synapses in human dorsolateral prefrontal cortex.

Coordinated activity of neural circuitry in the primate dorsolateral prefrontal cortex (DLPFC) supports a range of cognitive functions. Altered DLPFC activation is implicated in a number of human psychiatric and neurological illnesses. Proper DLPFC activity is, in part, maintained by two populations of neurons containing the calcium-binding protein parvalbumin (PV): local inhibitory interneurons that form Type II synapses, and long-range glutamatergic inputs from the thalamus that form Type I synapses. Understanding the contributions of each PV neuronal population to human DLPFC function requires a detailed examination of their anatomical properties. Consequently, we performed an electron microscopic analysis of (1) the distribution of PV immunoreactivity within the neuropil, (2) the properties of dendritic shafts of PV-IR interneurons, (3) Type II PV-IR synapses from PV interneurons, and (4) Type I PV-IR synapses from long-range projections, within the superficial and middle laminar zones of the human DLPFC. In both laminar zones, Type II PV-IR synapses from interneurons comprised ∼60% of all PV-IR synapses, and Type I PV-IR synapses from putative thalamocortical terminals comprised the remaining ∼40% of PV-IR synapses. Thus, the present study suggests that innervation from PV-containing thalamic nuclei extends across superficial and middle layers of the human DLPFC. These findings contrast with previous ultrastructural studies in monkey DLPFC where Type I PV-IR synapses were not identified in the superficial laminar zone. The presumptive added modulation of DLPFC circuitry by the thalamus in human may contribute to species-specific, higher-order functions.

Distribution of calcium-binding proteins parvalbumin and calbindin in the pigeon telencephalic auditory center

Immunoreactivity for calcium-binding proteins parvalbumin (PV) and calbindin (CB) was studied in the pigeon (Columba livia) telencephalic auditory center. All its regions displayed overlapping distribution patterns of PV and CB immunoreactivity, although in the central (L2) vs. peripheral (L1, L3, CMM) layers they were dissimilar. L2 and the inner L1 sublayer (L1i) were distinguished by a higher immunoreactivity of neuropil for both proteins and the presence (in L2) of numerous small densely packed granular-type cells: heavily stained PV-ir and, as a rule, poorly stained CB-ir neurons. In Lli, the number of neurons and the density of neuropil immunoreactive to both proteins decreased. The outer L1 sublayer (L1e) as well as L3 and CMM were characterized by a generally lesser density and irregular distribution of immunoreactive neuropil and a heterogenous repertoire of PV-ir and CB-ir neurons referring to diverse morphological types, with an increased number of large multipolar cells. The differences in PV and CB immunoreactivity among different regions of the pigeon telencephalic auditory center revealed the similarity of the latter to the laminar auditory cortex in mammals.

Distribution of type I corticotropin-releasing factor (CRF1) receptors on GABAergic neurons within the basolateral amygdala.

The neuropeptide corticotropin-releasing factor (CRF) plays a critical role in mediating anxiety-like responses to stressors, and dysfunction of the CRF system has been linked to the etiology of several psychiatric disorders. Extra-hypothalamic CRF can also modulate learning and memory formation, including amygdala-dependent learning. The basolateral nucleus of the amygdala (BLA) contains dense concentrations of CRF receptors, yet the distribution of these receptors on specific neuronal subtypes within the BLA has not been characterized. Here, we quantified the expression of CRF receptors on three nonoverlapping classes of GABAergic interneurons: those containing the calcium-binding protein parvalbumin (PV), and those expressing the neuropeptides somatostatin (SOM) or cholecystokinin (CCK). While the majority of PV+ neurons and roughly half of CCK+ neurons expressed CRF receptors, they were expressed to a much lesser extent on SOM+ interneurons. Knowledge of the distribution of CRF receptors within the BLA can provide insight into how manipulations of the CRF system modulate fear and anxiety-like behaviors.

Characterization of GABAergic Marker Expression in the Chronic Unpredictable Stress Model of Depression

Background Evidence continues to build suggesting that the GABAergic neurotransmitter system is altered in brains of patients with major depressive disorder. However, there is little information available related to the extent of these changes or the potential mechanisms associated with these alterations. As stress is a well-established precipitant to depressive episodes, we sought to explore the impact of chronic stress on GABAergic interneurons. Methods Using western blot analyses and quantitative real-time polymerase chain reaction, we assessed the effects of five-weeks of chronic unpredictable stress exposure on the expression of GABA-synthesizing enzymes (GAD65 and GAD67), calcium-binding proteins (calbindin, parvalbumin, and calretinin), and neuropeptides co-expressed in GABAergic neurons (somatostatin, neuropeptide Y, vasoactive intestinal peptide, and cholecystokinin) in the prefrontal cortex and hippocampus of rats. We also investigated the effects of corticosterone and dexamethasone exposure on these markers in vitro in primary cortical and hippocampal cultures. Results We found that chronic unpredictable stress induced significant reductions of GAD67 protein levels in both the prefrontal cortex and hippocampus of chronic unpredictable stress-exposed rats but did not detect changes in GAD65 protein expression. Similar protein expression changes were found in vitro in cortical neurons. In addition, our results provide clear evidence of reduced markers of interneuron population(s), namely somatostatin and neuropeptide Y, in the prefrontal cortex, suggesting these cell types may be selectively vulnerable to chronic stress. Conclusion Together, this work highlights that chronic stress induces regional and cell type-selective effects on GABAergic interneurons in rats. These findings provide additional supporting evidence that stress-induced GABA neuron dysfunction and cell vulnerability play critical roles in the pathophysiology of stress-related illnesses, including major depressive disorder.

Cocaine- and amphetamine–regulated transcript peptide and calcium binding proteins immunoreactivity in the superficial layers of the superior colliculus in the guinea pig: Implications for visual sensory processing

The purpose of this study was to investigate the distribution and colocalization of cocaine- and amphetamine-regulated transcript peptide (CART) and three calcium-binding proteins (calbindin, calretinin and parvalbumin) in the superficial layers of the superior colliculus (SCs) in the guinea pig. The CART immunoreactivity was observed exclusively in the solitary fibers and neuropil, which formed various CART-ir tiers, that corresponded partially or entirely to anatomically defined layers of the SCs. The CART-ir structures exhibited a characteristic morphology with bundles of densely intermingled neuronal fibers and terminals. This pattern of CART immunoreactivity in the visually driven SCs strongly indicates that CART peptide as a putative neurotransmitter may play an important role in processing of visual information. Double-labeling immunofluorescence showed that CART did not colocalize with either calcium binding proteins (CaBPs). Immunolabeling for CaBPs revealed the presence of different neuronal populations, which were concentrated in variously pronounced tiers. Contrary to CART, the CaBPs immunoreactivity in perikarya was relatively high and CaBPs containing neurons displayed a variety of sizes and somatodendritic morphologies. Generally, CaBPs patterns in the SCs of the guinea pig differ, to some extent, from those of other rodents. These results prove the importance of studying the neurochemical cytoarchitecture of diverse mammals.

Distribution of calcium-binding proteins parvalbumin and calbindin in the thalamic auditory center in pigeons

Distribution of calcium-binding proteins (CaBPr) parvalbumin (PV) and calbindin (CB) in the thalamic auditory center (nucleus ovoidalis, Ov) was studied in the pigeon (Columba livia). Two parts of Ov were distinguished on the basis of their cytoarchitectonics and distribution of PV and CB immunoreactivity. The central lemniscal region (core, nCe) contains both dense PV-ir neuropil and PV-ir neurons overlapped with scant CB-ir neuropil and weaker stained CB-ir neurons. The peripheral extralemniscal region (belt), consisting of peri/paraovoidal nuclei (Ovl, Ovm, SPO), contains only CB-ir neuropil and strongly stained CB-ir neurons morphologically differing from CB-ir neurons in the nCe. A comparative analysis of our data on the distribution of PV and CB immunoreactivity in the thalamic auditory relay center in pigeons and related literature data obtained on other avian, reptilian and mammalian species indicates high evolutionary conservatism of its extralemniscal region across all sauropside amniotеs and mammals in contrast to plasticity of its central lemniscal region due to adaptive, ecologically dependent transformations during the evolution.

Anatomical characterization of subcortical descending projections to the inferior colliculus in mouse.

Descending projections from the thalamus and related structures to the midbrain are evolutionarily highly conserved. However, the basic organization of this auditory thalamotectal pathway has not yet been characterized. The purpose of this study was to obtain a better understanding of the anatomical and neurochemical features of this pathway. Analysis of the distributions of retrogradely labeled cells after focal injections of retrograde tracer into the inferior colliculus (IC) of the mouse revealed that most of the subcortical descending projections originated in the brachium of the IC and the paralaminar portions of the auditory thalamus. In addition, the vast majority of thalamotectal cells were found to be negative for the calcium-binding proteins calbindin, parvalbumin, or calretinin. Using two different strains of GAD-GFP mice, as well as immunostaining for GABA, we found that a subset of neurons in the brachium of the IC is GABAergic, suggesting that part of this descending pathway is inhibitory. Finally, dual retrograde injections into the IC and amygdala plus corpus striatum as well into the IC and auditory cortex did not reveal any double labeling. These data suggest that the thalamocollicular pathway comprises a unique population of thalamic neurons that do not contain typical calcium-binding proteins and do not project to other paralaminar thalamic forebrain targets, and that a previously undescribed descending GABAergic pathway emanates from the brachium of the IC. J. Comp. Neurol. 525:885-900, 2017. © 2016 Wiley Periodicals, Inc.

A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a dreadful, devastating and incurable motor neuron disease. Aetiologically, it is a multigenic, multifactorial and multiorgan disease. Despite intense research, ALS pathology remains unexplained. Following extensive literature review, this paper posits a new integrative explanation. This framework proposes that ammonia neurotoxicity is a main player in ALS pathogenesis. According to this explanation, a combination of impaired ammonia removal— mainly because of impaired hepatic urea cycle dysfunction—and increased ammoniagenesis— mainly because of impaired glycolytic metabolism in fast twitch skeletal muscle—causes chronic hyperammonia in ALS. In the absence of neuroprotective calcium binding proteins (calbindin, calreticulin and parvalbumin), elevated ammonia—a neurotoxin—damages motor neurons. Ammonia-induced motor neuron damage occurs through multiple mechanisms such as macroautophagy-endolysosomal impairment, endoplasmic reticulum (ER) stress, CDK5 activation, oxidative/nitrosative stress, neuronal hyperexcitability and neuroinflammation. Furthermore, the regional pattern of calcium binding proteins’ loss, owing to either ER stress and/or impaired oxidative metabolism, determines clinical variability of ALS. Most importantly, this new framework can be generalised to explain other neurodegenerative disorders such as Huntington’s disease and Parkinsonism.