Anatomy and Neuroscience - Research Publications

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    Unidirectional monosynaptic connections from auditory areas to the primary visual cortex in the marmoset monkey
    Majka, P ; Rosa, MGP ; Bai, S ; Chan, JM ; Huo, B-X ; Jermakow, N ; Lin, MK ; Takahashi, YS ; Wolkowicz, IH ; Worthy, KH ; Rajan, R ; Reser, DH ; Wojcik, DK ; Okano, H ; Mitra, PP (SPRINGER HEIDELBERG, 2019-01-01)
    Until the late twentieth century, it was believed that different sensory modalities were processed by largely independent pathways in the primate cortex, with cross-modal integration only occurring in specialized polysensory areas. This model was challenged by the finding that the peripheral representation of the primary visual cortex (V1) receives monosynaptic connections from areas of the auditory cortex in the macaque. However, auditory projections to V1 have not been reported in other primates. We investigated the existence of direct interconnections between V1 and auditory areas in the marmoset, a New World monkey. Labelled neurons in auditory cortex were observed following 4 out of 10 retrograde tracer injections involving V1. These projections to V1 originated in the caudal subdivisions of auditory cortex (primary auditory cortex, caudal belt and parabelt areas), and targeted parts of V1 that represent parafoveal and peripheral vision. Injections near the representation of the vertical meridian of the visual field labelled few or no cells in auditory cortex. We also placed 8 retrograde tracer injections involving core, belt and parabelt auditory areas, none of which revealed direct projections from V1. These results confirm the existence of a direct, nonreciprocal projection from auditory areas to V1 in a different primate species, which has evolved separately from the macaque for over 30 million years. The essential similarity of these observations between marmoset and macaque indicate that early-stage audiovisual integration is a shared characteristic of primate sensory processing.
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    Claustrum projections to prefrontal cortex in the capuchin monkey (Cebus apella)
    Reser, DH ; Richardson, KE ; Montibeller, MO ; Zhao, S ; Chan, JMH ; Soares, JGM ; Chaplin, TA ; Gattass, R ; Rosa, MGP (FRONTIERS MEDIA SA, 2014-01-01)
    We examined the pattern of retrograde tracer distribution in the claustrum following intracortical injections into the frontal pole (area 10), and in dorsal (area 9), and ventral lateral (area 12) regions of the rostral prefrontal cortex in the tufted capuchin monkey (Cebus apella). The resulting pattern of labeled cells was assessed in relation to the three-dimensional geometry of the claustrum, as well as recent reports of claustrum-prefrontal connections in other primates. Claustrum-prefrontal projections were extensive, and largely concentrated in the ventral half of the claustrum, especially in the rostral 2/3 of the nucleus. Our data are consistent with a topographic arrangement of claustrum-cortical connections in which prefrontal and association cortices receive connections largely from the rostral and medial claustrum. Comparative aspects of claustrum-prefrontal topography across primate species and the implications of claustrum connectivity for understanding of cortical functional networks are explored, and we hypothesize that the claustrum may play a role in controlling or switching between resting state and task-associated cortical networks.
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    Venomics Reveals Venom Complexity of the Piscivorous Cone Snail, Conus tulipa
    Dutt, M ; Dutertre, S ; Jin, A-H ; Lavergne, V ; Alewood, PF ; Lewis, RJ (MDPI, 2019-01-01)
    The piscivorous cone snail Conus tulipa has evolved a net-hunting strategy, akin to the deadly Conus geographus, and is considered the second most dangerous cone snail to humans. Here, we present the first venomics study of C. tulipa venom using integrated transcriptomic and proteomic approaches. Parallel transcriptomic analysis of two C. tulipa specimens revealed striking differences in conopeptide expression levels (2.5-fold) between individuals, identifying 522 and 328 conotoxin precursors from 18 known gene superfamilies. Despite broad overlap at the superfamily level, only 86 precursors (11%) were common to both specimens. Conantokins (NMDA antagonists) from the superfamily B1 dominated the transcriptome and proteome of C. tulipa venom, along with superfamilies B2, A, O1, O3, con-ikot-ikot and conopressins, plus novel putative conotoxins precursors T1.3, T6.2, T6.3, T6.4 and T8.1. Thus, C. tulipa venom comprised both paralytic (putative ion channel modulating α-, ω-, μ-, δ-) and non-paralytic (conantokins, con-ikot-ikots, conopressins) conotoxins. This venomic study confirms the potential for non-paralytic conotoxins to contribute to the net-hunting strategy of C. tulipa.
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    The alpha(1)-adrenoceptor inhibitor rho-TIA facilitates net hunting in piscivorous Conus tulipa
    Dutt, M ; Giacomotto, J ; Ragnarsson, L ; Andersson, A ; Brust, A ; Dekan, Z ; Alewood, PF ; Lewis, RJ (NATURE PUBLISHING GROUP, 2019-11-28)
    Cone snails use separately evolved venoms for prey capture and defence. While most use a harpoon for prey capture, the Gastridium clade that includes the well-studied Conus geographus and Conus tulipa, have developed a net hunting strategy to catch fish. This unique feeding behaviour requires secretion of "nirvana cabal" peptides to dampen the escape response of targeted fish allowing for their capture directly by mouth. However, the active components of the nirvana cabal remain poorly defined. In this study, we evaluated the behavioural effects of likely nirvana cabal peptides on the teleost model, Danio rerio (zebrafish). Surprisingly, the conantokins (NMDA receptor antagonists) and/or conopressins (vasopressin receptor agonists and antagonists) found in C. geographus and C. tulipa venom failed to produce a nirvana cabal-like effect in zebrafish. In contrast, low concentrations of the non-competitive adrenoceptor antagonist ρ-TIA found in C. tulipa venom (EC50 = 190 nM) dramatically reduced the escape response of zebrafish larvae when added directly to aquarium water. ρ-TIA inhibited the zebrafish α1-adrenoceptor, confirming ρ-TIA has the potential to reverse the known stimulating effects of norepinephrine on fish behaviour. ρ-TIA may act alone and not as part of a cabal, since it did not synergise with conopressins and/or conantokins. This study highlights the importance of using ecologically relevant animal behaviour models to decipher the complex neurobiology underlying the prey capture and defensive strategies of cone snails.
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    Transcriptomic-Proteomic Correlation in the Predation-Evoked Venom of the Cone Snail, Conus imperialis.
    Jin, A-H ; Dutertre, S ; Dutt, M ; Lavergne, V ; Jones, A ; Lewis, RJ ; Alewood, PF (MDPI AG, 2019-03-19)
    Individual variation in animal venom has been linked to geographical location, feeding habit, season, size, and gender. Uniquely, cone snails possess the remarkable ability to change venom composition in response to predatory or defensive stimuli. To date, correlations between the venom gland transcriptome and proteome within and between individual cone snails have not been reported. In this study, we use 454 pyrosequencing and mass spectrometry to decipher the transcriptomes and proteomes of the venom gland and corresponding predation-evoked venom of two specimens of Conus imperialis. Transcriptomic analyses revealed 17 conotoxin gene superfamilies common to both animals, including 5 novel superfamilies and two novel cysteine frameworks. While highly expressed transcripts were common to both specimens, variation of moderately and weakly expressed precursor sequences was surprisingly diverse, with one specimen expressing two unique gene superfamilies and consistently producing more paralogs within each conotoxin gene superfamily. Using a quantitative labelling method, conotoxin variability was compared quantitatively, with highly expressed peptides showing a strong correlation between transcription and translation, whereas peptides expressed at lower levels showed a poor correlation. These results suggest that major transcripts are subject to stabilizing selection, while minor transcripts are subject to diversifying selection.
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    Acute Down-regulation of BDNF Signaling Does Not Replicate Exacerbated Amyloid-beta Levels and Cognitive Impairment Induced by Cholinergic Basal Forebrain Lesion
    Turnbull, MT ; Boskovic, Z ; Coulson, EJ (FRONTIERS MEDIA SA, 2018-02-22)
    Degeneration of basal forebrain cholinergic neurons (BFCNs) precedes hippocampal degeneration and pathological amyloid-beta (Aβ) accumulation, and underpins the development of cognitive dysfunction in sporadic Alzheimer's disease (AD). We hypothesized that degeneration of BFCNs causes a decrease in neurotrophin levels in innervated brain areas, which in turn promotes the development of Aβ pathology and cognitive impairment. Here we show that lesion of septo-hippocampal BFCNs in a pre-symptomatic transgenic amyloid AD mouse model (APP/PS1 mice) increases soluble Aβ levels in the hippocampus, and induces cognitive deficits in a spatial memory task that are not seen in either unlesioned APP/PS1 or non-transgenic littermate control mice. Furthermore, the BFCN lesion results in decreased levels of brain-derived neurotrophic factor (BDNF). However, viral knockdown of neuronal BDNF in the hippocampus of APP/PS1 mice (in the absence of BFCN loss) neither increased the level of Aβ nor caused cognitive deficits. These results suggest that the cognitive decline and Aβ pathology induced by BFCN loss occur independent of dysfunctional neuronal BDNF signaling, and may therefore be directly underpinned by reduced cholinergic neurotransmission.
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    Lesions of the Basal Forebrain Cholinergic System in Mice Disrupt Idiothetic Navigation
    Hamlin, AS ; Windels, F ; Boskovic, Z ; Sah, P ; Coulson, EJ ; Ginsberg, SD (PUBLIC LIBRARY SCIENCE, 2013-01-08)
    Loss of integrity of the basal forebrain cholinergic neurons is a consistent feature of Alzheimer's disease, and measurement of basal forebrain degeneration by magnetic resonance imaging is emerging as a sensitive diagnostic marker for prodromal disease. It is also known that Alzheimer's disease patients perform poorly on both real space and computerized cued (allothetic) or uncued (idiothetic) recall navigation tasks. Although the hippocampus is required for allothetic navigation, lesions of this region only mildly affect idiothetic navigation. Here we tested the hypothesis that the cholinergic medial septo-hippocampal circuit is important for idiothetic navigation. Basal forebrain cholinergic neurons were selectively lesioned in mice using the toxin saporin conjugated to a basal forebrain cholinergic neuronal marker, the p75 neurotrophin receptor. Control animals were able to learn and remember spatial information when tested on a modified version of the passive place avoidance test where all extramaze cues were removed, and animals had to rely on idiothetic signals. However, the exploratory behaviour of mice with cholinergic basal forebrain lesions was highly disorganized during this test. By contrast, the lesioned animals performed no differently from controls in tasks involving contextual fear conditioning and spatial working memory (Y maze), and displayed no deficits in potentially confounding behaviours such as motor performance, anxiety, or disturbed sleep/wake cycles. These data suggest that the basal forebrain cholinergic system plays a specific role in idiothetic navigation, a modality that is impaired early in Alzheimer's disease.
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    Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation
    Alder, O ; Cullum, R ; Lee, S ; Kan, AC ; Wei, W ; Yi, Y ; Garside, VC ; Bilenky, M ; Griffith, M ; Morrissy, AS ; Robertson, GA ; Thiessen, N ; Zhao, Y ; Chen, Q ; Pan, D ; Jones, SJM ; Marra, MA ; Hoodless, PA (CELL PRESS, 2014-10-09)
    Cell fate acquisition is heavily influenced by direct interactions between master regulators and tissue-specific enhancers. However, it remains unclear how lineage-specifying transcription factors, which are often expressed in both progenitor and mature cell populations, influence cell differentiation. Using in vivo mouse liver development as a model, we identified thousands of enhancers that are bound by the master regulators HNF4A and FOXA2 in a differentiation-dependent manner, subject to chromatin remodeling, and associated with differentially expressed target genes. Enhancers exclusively occupied in the embryo were found to be responsive to developmentally regulated TEAD2 and coactivator YAP1. Our data suggest that Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers. In summary, transcription factor-enhancer interactions are not only tissue specific but also differentiation dependent, which is an important consideration for researchers studying cancer biology or mammalian development and/or using transformed cell lines.
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    Relationship between ovarian cancer stem cells, epithelial mesenchymal transition and tumour recurrence.
    Padilla, MAA ; Binju, M ; Wan, G ; Rahmanto, YS ; Kaur, P ; Yu, Y (OAE Publishing Inc., 2019)
    Investigating the biological processes that occur to enable recurrence and the development of chemoresistance in ovarian cancer is critical to the research and development of improved treatment options for patients. The lethality of ovarian cancer is largely attributed to the recurrence of disease with acquired chemoresistance. Cancer stem cells are likely to be critical in ovarian cancer progression, contributing to tumour malignancy, metastasis and recurrence by persisting in the body despite treatment with anti-cancer drugs. Moreover, cancer stem cells are capable of mediating epithelial-to-mesenchymal transition traits and secrete extracellular vesicles to acquire therapy resistance and disease dissemination. These attributes merit in depth research to provide insight into the biological role of ovarian cancer stem cells in disease progression and chemotherapy response, leading to the development of improved biomarkers and innovative therapeutic approaches.
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    Current pharmacotherapies for sarcopenia
    Hardee, JP ; Lynch, GS (TAYLOR & FRANCIS LTD, 2019-05-25)
    Introduction: Sarcopenia, the age-related loss of skeletal muscle mass and function, is a global health problem that contributes to the development of physical disability, morbidity and mortality in the ageing population. Sarcopenia is now recognised in many countries as a muscle disease with an ICD-10-CM Diagnosis Code for billing care related to this condition, despite no FDA-approved treatments being currently available. Areas covered: This review highlights the current state of knowledge regarding the biological mechanisms contributing to the age-related loss of muscle mass and function and provides a summary of existing and emerging pharmacotherapies in clinical trials for sarcopenia. Expert opinion: While understanding of the pathophysiology of sarcopenia has progressed, rigorous preclinical studies that better inform clinical trials are needed to accelerate drug discovery and identify safe and effective treatments. Few drugs have been developed specifically for sarcopenia and many have failed to meet clinically relevant outcomes related to strength and physical performance. The multifactorial complexity of sarcopenia means that tailored, personalised treatments are more likely to be required than just a single intervention.