Regions Of Central Nervous System Research Articles

Gap Junctions and Epileptogenesis: No Laughing Matter

Gap Junctions and Epileptogenesis: No Laughing Matter

Artistic Skills Recovery and Compensation in Visual Artists after Stroke

Art is a characteristic of mankind, which requires superior central nervous processing and integration of motor functions with visual information. At the present time, a significant amount of information related to neurobiological basis of artistic creation has been derived from neuro-radiological cognitive studies, which have revealed that subsequent to tissue destruction, the artists continue to create art. The current study aims to review the most important cases of visual artists with stroke and to discuss artistic skills recovery and compensation as well as artistic style after stroke. The role of various central nervous system regions in artistic creation was reviewed on the basis of previously published functional studies. Our PubMed search (1995-2015) has identified 10 famous artists with right cerebral stroke as well as 5 with left cerebral stroke who survived and continued to create art after stroke. As the artists included in this review lived at various times during the twentieth century and in different countries, clinical information related to their case was limited. However, it appears that artistic skills recovery and compensation appear within days after stroke. Some of the artists would subsequently change their artistic style. All these elements have been evaluated within the context of specific clinical cases. The poststroke artistic skills recovery and compensation with development of a new style or the opposite, regaining the previous prestroke style, represents a significant element of clinical importance in medical rehabilitation as well as neuroesthetics, which requires further evaluation. At the present time, the molecular mechanisms of artistic creation are poorly understood, and more standardized clinical and experimental studies are needed.

252. Using Cre-Dependent In Vivo Selection to Identify AAV Variants That Enable Efficient and Widespread Gene Transfer to the Adult Central Nervous System

Recombinant adeno-associated viruses (rAAVs) are commonly used vehicles for in vivo gene transfer. However, the tropism repertoire of naturally occurring AAVs is limited, prompting the development of novel AAV capsids with more desirable transduction characteristics. We have developed a capsid selection method, called Cre-recombination-based AAV targeted evolution (CREATE), that enables the identification of AAV capsids that more efficiently transduce defined cell populations in vivo (Deverman et al. in press, Nature Biotechnology). We generated AAV capsid libraries and used CREATE to identify variants that cross the blood brain barrier and efficiently and widely transduce astrocytes in the mouse central nervous system (CNS) after intravenous injection. One variant, AAVPHP. B, transfers genes throughout the adult CNS with an efficiency that is 40- to 92-fold greater (depending on the CNS region) than that of the current standard, AAV9. It transduces the majority of astrocytes and neurons across multiple CNS regions, and in vitro, it transduces human neurons and astrocytes more efficiently than does AAV9. We are now evolving AAV-PHP.B for even greater transduction of specific CNS cell types as a means to both develop more effective vectors and to gain insight into the mechanism of enhanced transduction. Our identification of AAV-PHP.B and several other enhanced vectors after only two rounds of selection establishes CREATE as a powerful method to customize AAV vectors for biomedical applications.

Involvement of toll-like receptors 3 and 7/8 in the neuropathogenesis of bovine herpesvirus types 1 and 5

Bovine herpesvirus types 1 (BoHV-1) and 5 (BoHV-5) are closely related alpha-herpesviruses. BoHV-5 is the causal agent of non-suppurative meningoencephalitis in calves. BoHV-1 causes respiratory disease, abortions, genital disorders and, occasionally, encephalitis in cattle. Both viruses are neurotropic and they share similar biological properties. Nevertheless, they differ in their ability to cause neurological disease. Toll-like receptors (TLRs) are involved in the innate immune response to pathogens. In this study, the variations in the expression levels of TLRs were evaluated in different regions of the bovine central nervous system during the acute infection and reactivation of BoHV-1 and BoHV-5- infected cattle. With the exception of TLR9, significant up-regulation of all TLRs was detected following primary infection of neural tissues by both bovine alpha-herpesviruses. Furthermore, the stages of acute infection and reactivation were characterized by a distinguishable TLR expression pattern. Important differences in TLR expression upon infection of the central nervous system by BoHV-1 or BoHV-5 were not detected. The striking differences in TLR mRNA levels during acute infection and reactivation provide evidence that the innate immune response may be involved in the clinical outcomes observed at each stage. Further research is required to analyze the mechanisms that initiate TLR activation and the signaling cascade mediated by each TLR to elucidate the precise role these receptors play in bovine herpesvirus encephalitis.

Dynamic secondary degeneration in the spinal cord and ventral root after a focal cerebral infarction among hypertensive rats.

Cerebral infarction can cause secondary damage to nonischemic brain regions. However, whether this phenomenon will appear in central nervous system regions outside the brain remains unclear. Here we investigated pathological changes in the spinal cord and ventral root after ischemic stroke. All rats exhibited apparent neurological deficits post-MCAO, which improved gradually but could still be detected 12-weeks. Neuronal filaments in the corticospinal tract (CST) and neurons in the ventral horn were significantly declined in the contralateral cervical and lumbar enlargement 1-week post-MCAO. These decreases remained stable until 12-weeks, accompanied by progressively increased glial activation in the ventral horn. Axonal degeneration and structural derangement were evident in the contralateral cervical and lumbar ventral root 1-week post-MCAO; these changes spontaneously attenuated over time, but abnormalities could still be observed 12-weeks. The number of neural fibers in the contralateral CST and neurons in the contralateral ventral horn were positively correlated with neurological scores 12-weeks post-MCAO. Additionally, GFAP+cell density in the contralateral CST and ventral horn was negatively correlated with neurological scores. Our results suggest that cerebral infarction can elicit secondary degeneration in the cervical and lumbar spinal cord, as well as the projecting ventral root, which may hamper functional recovery after stroke.

Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain

Recombinant adeno-associated viruses (rAAVs) are commonly used vehicles for in vivo gene transfer1-6. However, the tropism repertoire of naturally occurring AAVs is limited, prompting a search for novel AAV capsids with desired characteristics7-13. Here we describe a capsid selection method, called Cre-recombination-based AAV targeted evolution (CREATE), that enables the development of AAV capsids that more efficiently transduce defined Cre-expressing cell populations in vivo. We use CREATE to generate AAV variants that efficiently and widely transduce the adult mouse central nervous system (CNS) after intravenous injection. One variant, AAV-PHP.B, transfers genes throughout the CNS with an efficiency that is at least 40-fold greater than that of the current standard, AAV914-17, and transduces the majority of astrocytes and neurons across multiple CNS regions. In vitro, it transduces human neurons and astrocytes more efficiently than does AAV9, demonstrating the potential of CREATE to produce customized AAV vectors for biomedical applications.

CNS-wide Sexually Dimorphic Induction of the Major Histocompatibility Complex 1 Pathway With Aging.

The major histocompatibility complex I (MHCI) pathway, which canonically functions in innate immune viral antigen presentation and detection, is functionally pleiotropic in the central nervous system (CNS). Alternative roles include developmental synapse pruning, regulation of synaptic plasticity, and inhibition of neuronal insulin signaling; all processes altered during brain aging. Upregulation of MHCI components with aging has been reported; however, no systematic examination of MHCI cellular localization, expression, and regulation across CNS regions, life span, and sexes has been reported. In the mouse, MHCI is expressed by neurons and microglia, and MHCI components and receptors (H2-K1, H2-D1, β2M, Lilrb3, Klra2, CD247) display markedly different expression profiles across the hippocampus, cortex, cerebellum, brainstem, and retina. MHCI components, receptors, associated inflammatory transcripts (IL1α, IL1β, IL6, TNFα), and TAP (transporter associated with antigen processing) components are induced with aging and to a greater degree in female than male mice across CNS regions. H2-K1 and H2-D1 expression is associated with differential CG and non-CG promoter methylation across CNS regions, ages, and between sexes, and concomitant increased expression of proinflammatory genes. Meta-analysis of human brain aging data also demonstrates age-related increases in MHCI. Induction of MHCI signaling could contribute to altered synapse regulation and impaired synaptic plasticity with aging.

Sex and estrogens alter the action of glucagon-like peptide-1 on reward.

BackgroundFeeding behavior is regulated through an intricate array of anorexic and orexigenic hormones acting on the central nervous system (CNS). Some of these hormones may have differential effects in males and females, effects potentially attributed to actions of gonadal steroids, especially estrogens. Central stimulation of the glucagon-like peptide-1 (GLP-1) receptors reduces feeding and food-reward behavior by acting on CNS regions important for the anorexic actions of estrogens. Thus, we propose that the action of GLP-1 on food intake and reward may differ between sexes.MethodsMale and female rats were centrally injected with the GLP-1 analog exendin-4 (Ex4) in a non-deprived or food-restricted state; reward behavior was measured in a progressive ratio operant conditioning task. Intake of chow and palatable food were also measured. To determine if sex differences in the actions of Ex4 are due to interactions with estrogens, Ex4 treatment was preceded by treatment with a nonselective estrogen receptor-α (ERα) and ERβ or ERα-selective antagonist.ResultsCentral injection of Ex4 revealed increased reward behavior suppression in females, compared to males, in the operant conditioning task. This increase was present in both non-deprived and food-restricted animals with larger differences in the fed state. Intake of chow and palatable food, after Ex4, were similar in males and females. Food reward, but not food intake, effect of Ex4 was attenuated by pretreatment with ER antagonist in both sexes, suggesting that estrogens may modulate effects of Ex4 in both sexes. Furthermore, central pretreatment with ERα-selective antagonist was sufficient to attenuate effects of Ex4 on reward.ConclusionsCollectively, these data reveal that females display much higher sensitivity to the food reward impact of central GLP-1 receptor activation. Surprisingly, they also demonstrate that central ERα signaling is necessary for the actions of GLP-1 on food-reward behavior in both sexes.

Age-Related Expression of a Repeat-Rich Intergenic Long Noncoding RNA in the Rat Brain.

Genome-wide transcriptome analysis has shown that ∼90% of the mammalian genome undergoes pervasive transcription into various small and long noncoding RNAs with diverse biological functions and only ∼1.5% is protein coding. Recent literature suggests that various structurally diverse sense and antisense long noncoding RNAs (lncRNAs) (>200nt) are expressed from the intronic, intergenic and repeat-rich regions in the mammalian central nervous system (CNS). Till date, many of them have been found to be regulated in developmental, spatio-temporal and cell type-specific manners and are involved in various neurological processes. However, still much is left to be understood regarding their functional relevance in mammalian brain development, maturation and ageing. Furthermore, various signalling factors and metabolites such as all-trans retinoic acid (atRA) have been known to regulate brain functions during development, though their role in adult brain function is much less known. Here, we report differential and age-related expression of a novel repeat sequence-rich, long intergenic nonprotein coding RNA (lincRNA), named as LINC-RSAS (repeat-rich sense-antisense transcript) in different neuroanatomical regions of the rat brain. The LINC-RSAS was found to be moderately conserved and contained regulatory elements of various cell growth- and development-specific transcriptional factors in its up/downstream flanking sequences in the genome. Through RNA expression by reverse transcription polymerase chain reaction (RT-PCR) and localization by in situ RNA hybridization, we found that both sense and antisense transcripts of LINC-RSAS were expressed in the cortex, hippocampus and cerebellum regions of the rat brain in cell type-specific and age-related manner. Furthermore, both the expression level and subcellular localization of the antisense LINC-RSAS transcript were significantly induced in the cultured primary hippocampal neurons after treatment with atRA. Overall, our study provides insights into the possible involvement of an atRA-inducible, intergenic lncRNA in different functional regions of mammalian brain and its association with brain maturation and ageing.

Interleukin-1β overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents.

BackgroundChronic pain is often accompanied by short-term memory deficit and depression. Currently, it is believed that short-term memory deficit and depression are consequences of chronic pain. Here, we test the hypothesis that the symptoms might be caused by overproduction of interleukin-1beta (IL-1β) in the injured nerve independent of neuropathic pain following spared nerve injury in rats and mice.ResultsMechanical allodynia, a behavioral sign of neuropathic pain, was not correlated with short-term memory deficit and depressive behavior in spared nerve injury rats. Spared nerve injury upregulated IL-1β in the injured sciatic nerve, plasma, and the regions in central nervous system closely associated with pain, memory and emotion, including spinal dorsal horn, hippocampus, prefrontal cortex, nucleus accumbens, and amygdala. Importantly, the spared nerve injury-induced memory deficits, depressive, and pain behaviors were substantially prevented by peri-sciatic administration of IL-1β neutralizing antibody in rats or deletion of IL-1 receptor type 1 in mice. Furthermore, the behavioral abnormalities induced by spared nerve injury were mimicked in naïve rats by repetitive intravenous injection of re combinant rat IL-1β (rrIL-1β) at a pathological concentration as determined from spared nerve injury rats. In addition, microglia were activated by both spared nerve injury and intravenous injection of rrIL-1β and the effect of spared nerve injury was substantially reversed by peri-sciatic administration of anti-IL-1β.ConclusionsNeuropathic pain was not necessary for the development of cognitive and emotional disorders, while the overproduction of IL-1β in the injured sciatic nerve following peripheral nerve injury may be a common mechanism underlying the generation of neuropathic pain, memory deficit, and depression.

Molecular imaging of movement disorders.

Positron emission tomography measures the activity of radioactively labeled compounds which distribute and accumulate in central nervous system regions in proportion to their metabolic rate or blood flow. Specific circuits such as the dopaminergic nigrostriatal projection can be studied with ligands that bind to the pre-synaptic dopamine transporter or post-synaptic dopamine receptors (D1 and D2). Single photon emission computerized tomography (SPECT) measures the activity of similar tracers labeled with heavy radioactive species such as technetium and iodine. In essential tremor, there is cerebellar hypermetabolism and abnormal GABAergic function in premotor cortices, dentate nuclei and ventral thalami, without significant abnormalities in dopaminergic transmission. In Huntington's disease, there is hypometabolism in the striatum, frontal and temporal cortices. Disease progression is accompanied by reduction in striatal D1 and D2 binding that correlates with trinucleotide repeat length, disease duration and severity. In dystonia, there is hypermetabolism in the basal ganglia, supplementary motor areas and cerebellum at rest. Thalamic and cerebellar hypermetabolism is seen during dystonic movements, which can be modulated by globus pallidus deep brain stimulation (DBS). Additionally, GABA-A receptor activity is reduced in motor, premotor and somatosensory cortices. In Tourette's syndrome, there is hypermetabolism in premotor and sensorimotor cortices, as well as hypometabolism in the striatum, thalamus and limbic regions at rest. During tics, multiple areas related to cognitive, sensory and motor functions become hypermetabolic. Also, there is abnormal serotoninergic transmission in prefrontal cortices and bilateral thalami, as well as hyperactivity in the striatal dopaminergic system which can be modulated with thalamic DBS. In Parkinson's disease (PD), there is asymmetric progressive decline in striatal dopaminergic tracer accumulation, which follows a caudal-to-rostral direction. Uptake declines prior to symptom presentation and progresses from contralateral to the most symptomatic side to bilateral, correlating with symptom severity. In progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), striatal activity is symmetrically and diffusely decreased. The caudal-to-rostral pattern is lost in PSP, but could be present in MSA. In corticobasal degeneration (CBD), there is asymmetric, diffuse reduction of striatal activity, contralateral to the most symptomatic side. Additionally, there is hypometabolism in contralateral parieto-occipital and frontal cortices in PD; bilateral putamen and cerebellum in MSA; caudate, thalamus, midbrain, mesial frontal and prefrontal cortices in PSP; and contralateral cortices in CBD. Finally, cardiac sympathetic SPECT signal is decreased in PD. The capacity of molecular imaging to provide in vivo time courses of gene expression, protein synthesis, receptor and transporter binding, could facilitate the development and evaluation of novel medical, surgical and genetic therapies in movement disorders.

Histamine and Immune Biomarkers in CNS Disorders.

Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS) disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56) which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA) is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimer's disease (AD). Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic) in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1β, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death.

Ginsenoside Rg1 attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced parkinsonism mouse model by targeting α-synuclein abnormalities in the substantia nigra.

Parkinson's disease (PD) is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of aggregated α-synuclein in specific central nervous system (CNS) regions. Disease development is attributed to α-synuclein abnormalities, particularly aggregation and phosphorylation. The ginsenoside Rg1, an active component of ginseng, possesses neuroprotective and anti-inflammatory effects. The purpose of the present study was to evaluate these activities of Rg1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid (MPTP/p)-induced PD mouse model for the first time and to elucidate the underlying mechanisms. Oral treatment with Rg1 significantly attenuated the high MPTP-induced mortality, behavior defects, loss of dopamine neurons and abnormal ultrastructure changes in the SNpc. Other assays indicated that the protective effect of Rg1 may be mediated by its anti-neuroinflammatory properties. Rg1 regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the SNpc. Rg1 also alleviated the unusual MPTP-induced increase in oligomeric, phosphorylated and disease-related α-synuclein in the SNpc. In conclusion, Rg1 protects dopaminergic neurons, most likely by reducing aberrant α-synuclein-mediated neuroinflammation, and holds promise for PD therapeutics.

Anatomical and ultrastructural study of PRAF2 expression in the mouse central nervous system.

Prenylated Rab acceptor family, member 2 (PRAF2) is a four transmembrane domain protein of 19kDa that is highly expressed in particular areas of mammalian brains. PRAF2 is mostly found in the endoplasmic reticulum (ER) of neurons where it plays the role of gatekeeper for the GB1 subunit of the GABAB receptor, preventing its progression in the biosynthetic pathway in the absence of hetero-dimerization with the GB2 subunit. However, PRAF2 can interact with several receptors and immunofluorescence studies indicate that PRAF2 distribution is larger than the ER, suggesting additional biological functions. Here, we conducted an immuno-cytochemical study of PRAF2 distribution in mouse central nervous system (CNS) at anatomical, cellular and ultra-structural levels. PRAF2 appears widely expressed in various regions of mature CNS, such as the olfactory bulbs, cerebral cortex, amygdala, hippocampus, ventral tegmental area and spinal cord. Consistent with its regulatory role of GABAB receptors, PRAF2 was particularly abundant in brain regions known to express GB1 subunits. However, other brain areas where GB1 is expressed, such as basal ganglia, thalamus and hypothalamus, contain little or no PRAF2. In these areas, GB1 subunits might reach the cell surface of neurons independently of GB2 to exert biological functions distinct from those of GABAB receptors, or be regulated by other gatekeepers. Electron microscopy studies confirmed the localization of PRAF2 in the ER, but identified previously unappreciated localizations, in mitochondria, primary cilia and sub-synaptic region. These data indicate additional modes of GABAB regulation in specific brain areas and new biological functions of PRAF2.

Noncanonical Sites of Adult Neurogenesis in the Mammalian Brain.

Two decades after the discovery that neural stem cells (NSCs) populate some regions of the mammalian central nervous system (CNS), deep knowledge has been accumulated on their capacity to generate new neurons in the adult brain. This constitutive adult neurogenesis occurs throughout life primarily within remnants of the embryonic germinal layers known as "neurogenic sites." Nevertheless, some processes of neurogliogenesis also occur in the CNS parenchyma commonly considered as "nonneurogenic." This "noncanonical" cell genesis has been the object of many claims, some of which turned out to be not true. Indeed, it is often an "incomplete" process as to its final outcome, heterogeneous by several measures, including regional location, progenitor identity, and fate of the progeny. These aspects also strictly depend on the animal species, suggesting that persistent neurogenic processes have uniquely adapted to the brain anatomy of different mammals. Whereas some examples of noncanonical neurogenesis are strictly parenchymal, others also show stem cell niche-like features and a strong link with the ventricular cavities. This work will review results obtained in a research field that expanded from classic neurogenesis studies involving a variety of areas of the CNS outside of the subventricular zone (SVZ) and subgranular zone (SGZ). It will be highlighted how knowledge concerning noncanonical neurogenic areas is still incomplete owing to its regional and species-specific heterogeneity, and to objective difficulties still hampering its full identification and characterization.

Cannabinoid receptor 1 modulates the autophagic flux in a non-canonic fashion

Cannabinoid Receptor 1 (CBR1) has been initially described as the receptor for Δ9-THC in the central nervous system (CNS), mediating retrograde synaptic signaling exerted by the endocannabinoid system. CBR1 is expressed in different CNS regions, but is also present in a variety of peripheral tissues, where one well described function of CBR1 there is the direct modulation of the energy homeostasis of the cell. A main constituent contributing to the regulation of the intracellular energy status is the evolutionary conserved autophagic machinery, which is in addition an important cellular degradation pathway and thereby a regulator for protein homeostasis. This prompted us to examine the role of CBR1 in the control of autophagic activity in mammalian cells. Manipulating CBR1 activity caused an elevated autophagic flux, while the expression of autophagy-related genes remained unaltered. This effect was independent of mTORC1, known as major switch in the control of canonical autophagy. In addition, knocking down key-components of the BECLIN1-complex, which is the second canonical autophagy control complex, is not sufficient to reduce the CBR1 dependent modulation of the autophagic flux. Therefore, CBR1 activity seems to affect the autophagic flux in a non-canonic fashion and might be a pharamacological target for clinical use to modulate the autophagic activity as a novel treatment strategy for pathological states, which are linked to a disturbed autophagic function.

Glaucoma as a neurodegenerative disease.

The primary pathophysiological feature of glaucoma is a progressive optic neuropathy with characteristic morphological changes of the optic disc and risk factors of age and intraocular pressure. Recently, involvement of other areas of the central nervous system (CNS) beyond the optic nerve has been demonstrated. This article addresses the proposition that glaucoma shares mechanistic and pathophysiologic features with neurodegenerations in the CNS. The literature on CNS alterations in patients with glaucoma is reviewed with particular focus on neuroimaging and pathological studies. A theoretical framework for assessing whether glaucoma is truly a neurodegenerative disease is developed based on the comparison with neurodegenerative and nonneurodegenerative diseases. Although there is convincing evidence of abnormalities in CNS regions distal to the optic nerve in glaucoma, these are similar to those seen in other disorders of the proximal visual pathways, such as other optic neuropathies or retinal diseases. Similarly, features of glaucoma that are similar to neurodegenerations are also seen in nonneurodegenerative diseases. Glaucoma is less likely a primary neurodegeneration affecting the CNS and more likely a primary optic neuropathy with secondary effects in the CNS.

Whole-central nervous system functional imaging in larval Drosophila.

Understanding how the brain works in tight concert with the rest of the central nervous system (CNS) hinges upon knowledge of coordinated activity patterns across the whole CNS. We present a method for measuring activity in an entire, non-transparent CNS with high spatiotemporal resolution. We combine a light-sheet microscope capable of simultaneous multi-view imaging at volumetric speeds 25-fold faster than the state-of-the-art, a whole-CNS imaging assay for the isolated Drosophila larval CNS and a computational framework for analysing multi-view, whole-CNS calcium imaging data. We image both brain and ventral nerve cord, covering the entire CNS at 2 or 5 Hz with two- or one-photon excitation, respectively. By mapping network activity during fictive behaviours and quantitatively comparing high-resolution whole-CNS activity maps across individuals, we predict functional connections between CNS regions and reveal neurons in the brain that identify type and temporal state of motor programs executed in the ventral nerve cord.

Rhomboid Enhancer Activity Defines a Subset of Drosophila Neural Precursors Required for Proper Feeding, Growth and Viability.

Organismal growth regulation requires the interaction of multiple metabolic, hormonal and neuronal pathways. While the molecular basis for many of these are well characterized, less is known about the developmental origins of growth regulatory structures and the mechanisms governing control of feeding and satiety. For these reasons, new tools and approaches are needed to link the specification and maturation of discrete cell populations with their subsequent regulatory roles. In this study, we characterize a rhomboid enhancer element that selectively labels four Drosophila embryonic neural precursors. These precursors give rise to the hypopharyngeal sensory organ of the peripheral nervous system and a subset of neurons in the deutocerebral region of the embryonic central nervous system. Post embryogenesis, the rhomboid enhancer is active in a subset of cells within the larval pharyngeal epithelium. Enhancer-targeted toxin expression alters the morphology of the sense organ and results in impaired larval growth, developmental delay, defective anterior spiracle eversion and lethality. Limiting the duration of toxin expression reveals differences in the critical periods for these effects. Embryonic expression causes developmental defects and partially penetrant pre-pupal lethality. Survivors of embryonic expression, however, ultimately become viable adults. In contrast, post-embryonic toxin expression results in fully penetrant lethality. To better define the larval growth defect, we used a variety of assays to demonstrate that toxin-targeted larvae are capable of locating, ingesting and clearing food and they exhibit normal food search behaviors. Strikingly, however, following food exposure these larvae show a rapid decrease in consumption suggesting a satiety-like phenomenon that correlates with the period of impaired larval growth. Together, these data suggest a critical role for these enhancer-defined lineages in regulating feeding, growth and viability.

Neural Transplantation: Evidence from the Rodent Cerebellum1)

The transplantation of neural progenitors or stem cells has been attempted for several decades, in many regions of the central nervous system (CNS), to repair tissue damage or cell degeneration. In most circumstances the success of cell replacement in the brain depends on the capability to rewire precisely patterned connections. Several concurrent factors determine the outcome and efficacy of this approach, including the intrinsic properties of donor progenitors, the environmental cues provided by the recipient environment, and the complexity and precision of the connection patterns that must be restored in order to recover adaptive function. In this chapter, some major concepts concerning these issues are reviewed, with special attention being paid to studies involving neural transplantation in the rodent cerebellum and in animal models of cerebellar disorders. These approaches are considered the most suitable for the design and testing of cell-based therapeutic approaches aimed at reconstructing specific connections in point-to-point circuits. Keywords: neural transplantation; cell replacement; fate potential; cell specification; integration