Browsing by Author "Monavarfeshani, Aboozar"
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- Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortexSu, Jianmin; Chen, Jiang; Lippold, Kumiko; Monavarfeshani, Aboozar; Carrillo, Gabriela Lizana; Jenkins, Rchael; Fox, Michael A. (Rockefeller University Press, 2016-03-14)Inhibitory synapses comprise only ∼20% of the total synapses in the mammalian brain but play essential roles in controlling neuronal activity. In fact, perturbing inhibitory synapses is associated with complex brain disorders, such as schizophrenia and epilepsy. Although many types of inhibitory synapses exist, these disorders have been strongly linked to defects in inhibitory synapses formed by Parvalbumin-expressing interneurons. Here, we discovered a novel role for an unconventional collagen—collagen XIX—in the formation of Parvalbumin+ inhibitory synapses. Loss of this collagen results not only in decreased inhibitory synapse number, but also in the acquisition of schizophrenia-related behaviors. Mechanistically, these studies reveal that a proteolytically released fragment of this collagen, termed a matricryptin, promotes the assembly of inhibitory nerve terminals through integrin receptors. Collectively, these studies not only identify roles for collagen-derived matricryptins in cortical circuit formation, but they also reveal a novel paracrine mechanism that regulates the assembly of these synapses.
- F-spondin Is Essential for Maintaining Circadian RhythmsCarrillo, Gabriela Lizana; Su, Jianmin; Monavarfeshani, Aboozar; Fox, Michael A. (Frontiers, 2018-02-08)The suprachiasmatic nucleus (SCN) is the master pacemaker that drives circadian behaviors. SCN neurons have intrinsic, self-sustained rhythmicity that is governed by transcription-translation feedback loops. Intrinsic rhythms within the SCN do not match the day-night cycle and are therefore entrained by light-derived cues. Such cues are transmitted to the SCN by a class of intrinsically photosensitive retinal ganglion cells (ipRGCs). In the present study, we sought to identify how axons from ipRGCs target the SCN. While none of the potential targeting cues identified appeared necessary for retinohypothalamic innervation, we unexpectedly identified a novel role for the extracellular matrix protein F-spondin in circadian behavior. In the absence of F-spondin, mice lost their ability to maintain typical intrinsic rhythmicity. Moreover, F-spondin loss results in the displacement of vasoactive intestinal peptide (VIP)-expressing neurons, a class of neurons that are essential for maintaining rhythmicity among SCN neurons. Thus, this study highlights a novel role for F-spondin in maintaining circadian rhythms.
- LRRTM1 underlies synaptic convergence in visual thalamusMonavarfeshani, Aboozar; Stanton, Gail; Van Name, Jonathan; Su, Kaiwen; Mills, William A. III; Swilling, Kenya; Kerr, Alicia; Huebschman, Natalie A.; Su, Jianmin; Fox, Michael A. (eLife, 2018-02-09)It has long been thought that the mammalian visual system is organized into parallel pathways, with incoming visual signals being parsed in the retina based on feature (e.g. color, contrast and motion) and then transmitted to the brain in unmixed, feature-specific channels. To faithfully convey feature-specific information from retina to cortex, thalamic relay cells must receive inputs from only a small number of functionally similar retinal ganglion cells. However, recent studies challenged this by revealing substantial levels of retinal convergence onto relay cells. Here, we sought to identify mechanisms responsible for the assembly of such convergence. Using an unbiased transcriptomics approach and targeted mutant mice, we discovered a critical role for the synaptic adhesion molecule Leucine Rich Repeat Transmembrane Neuronal 1 (LRRTM1) in the emergence of retinothalamic convergence. Importantly, LRRTM1 mutant mice display impairment in visual behaviors, suggesting a functional role of retinothalamic convergence in vision.
- Mechanisms underlying retinogeniculate synapse formation in mouse visual thalamusMonavarfeshani, Aboozar (Virginia Tech, 2018-01-22)Retinogeniculate (RG) synapses connect retinal ganglion cells to the thalamic relay cells of the dorsal lateral geniculate nucleus (dLGN). They are critical for regulating the flow of visual information from retina to primary visual cortex (V1). RG synapses in dLGN are uniquely larger and stronger than their counterparts in other retinorecipient regions. Moreover, in dLGN, RG synapses can be classified into two groups: simple RG synapses, which contain glia-encapsulated single RTs synapsing onto relay cell dendrites, and complex RG synapses, which contain numerous RTs that converge onto the shared regions of relay cell dendrites. To identify target-derived molecules that direct the transformation of RTs into unique RG synapses in dLGN, I used RNAseq to obtain the whole transcriptome of dLGN and its adjacent retinorecipient nucleus, vLGN, at different time points during RG synapses development. Leucine-Rich Repeat Transmembrane Neuronal 1 (LRRTM1), a synaptogenic adhesion molecule, was the candidate I selected based on its expression pattern. Here, I discovered that LRRTM1 regulates the development of complex RG synapses. Mice lacking LRRTM1 (lrrtm1-/-) not only show a significant reduction in the number of complex RG synapses but they exhibit abnormal visual behaviors. This work reveals, for the first time, a high level of retinal convergence onto dLGN relay cells in thalamus and the functional significance of this convergence for vision.
- Multiple Retinal Axons Converge onto Relay Cells in the Adult Mouse ThalamusHammer, Sarah; Monavarfeshani, Aboozar; Lemon, Tyler; Su, Jianmin; Fox, Michael A. (Cell, 2015)Activity-dependent refinement of neural circuits is a fundamental principle of neural development. This process has been well studied at retinogeniculate synapses—synapses that form between retinal ganglion cells (RGCs) and relay cells within the dorsal lateral geniculate nucleus. Physiological studies suggest that shortly after birth, inputs from _20 RGCs converge onto relay cells. Subsequently, all but just one to two of these inputs are eliminated. Despite widespread acceptance, this notion is at odds with ultrastructural studies showing numerous retinal terminals clustering onto relay cell dendrites in the adult. Here, we explored this discrepancy using brainbow AAVs and serial block face scanning electron microscopy (SBFSEM). Results with both approaches demonstrate that terminals from numerous RGCs cluster onto relay cell dendrites, challenging the notion that only one to two RGCs innervate each relay cell. These findings force us to re-evaluate our understanding of subcortical visual circuitry.
- Nuclei-specific differences in nerve terminal distribution, morphology, and development in mouse visual thalamusHammer, Sarah; Carrillo, Gabriela Lizana; Govindaiah, Gubbi; Monavarfeshani, Aboozar; Bircher, Joseph S.; Su, Jianmin; Guido, William; Fox, Michael A. (BMC, 2014)Background: Mouse visual thalamus has emerged as a powerful model for understanding the mechanisms underlying neural circuit formation and function. Three distinct nuclei within mouse thalamus receive retinal input, the dorsal lateral geniculate nucleus (dLGN), the ventral lateral geniculate nucleus (vLGN), and the intergeniculate nucleus (IGL). However, in each of these nuclei, retinal inputs are vastly outnumbered by nonretinal inputs that arise from cortical and subcortical sources. Although retinal and nonretinal terminals associated within dLGN circuitry have been well characterized, we know little about nerve terminal organization, distribution and development in other nuclei of mouse visual thalamus. Results: Immunolabeling specific subsets of synapses with antibodies against vesicle-associated neurotransmitter transporters or neurotransmitter synthesizing enzymes revealed significant differences in the composition, distribution and morphology of nonretinal terminals in dLGN, vLGN and IGL. For example, inhibitory terminals are more densely packed in vLGN, and cortical terminals are more densely distributed in dLGN. Overall, synaptic terminal density appears least dense in IGL. Similar nuclei-specific differences were observed for retinal terminals using immunolabeling, genetic labeling, axonal tracing and serial block face scanning electron microscopy: retinal terminals are smaller, less morphologically complex, and more densely distributed in vLGN than in dLGN. Since glutamatergic terminal size often correlates with synaptic function, we used in vitro whole cell recordings and optic tract stimulation in acutely prepared thalamic slices to reveal that excitatory postsynaptic currents (EPSCs) are considerably smaller in vLGN and show distinct responses following paired stimuli. Finally, anterograde labeling of retinal terminals throughout early postnatal development revealed that anatomical differences in retinal nerve terminal structure are not observable as synapses initially formed, but rather developed as retinogeniculate circuits mature. Conclusions: Taken together, these results reveal nuclei-specific differences in nerve terminal composition, distribution, and morphology in mouse visual thalamus. These results raise intriguing questions about the different functions of these nuclei in processing light-derived information, as well as differences in the mechanisms that underlie their unique, nuclei-specific development.
- Pericyte heterogeneity identified by 3D ultrastructural analysis of the microvessel wallAbdelazim, Hanaa; Payne, Laura Beth; Nolan, Kyle; Paralkar, Karan; Bradley, Vanessa; Kanodia, Ronak; Gude, Rosalie; Ward, Rachael; Monavarfeshani, Aboozar; Fox, Michael A.; Chappell, John C. (Frontiers, 2022-12-16)Confident identification of pericytes (PCs) remains an obstacle in the field, as a single molecular marker for these unique perivascular cells remains elusive. Adding to this challenge is the recent appreciation that PC populations may be heterogeneous, displaying a range of morphologies within capillary networks. We found additional support on the ultrastructural level for the classification of these PC subtypes—“thin-strand” (TSP), mesh (MP), and ensheathing (EP)—based on distinct morphological characteristics. Interestingly, we also found several examples of another cell type, likely a vascular smooth muscle cell, in a medial layer between endothelial cells (ECs) and pericytes (PCs) harboring characteristics of the ensheathing type. A conserved feature across the different PC subtypes was the presence of extracellular matrix (ECM) surrounding the vascular unit and distributed in between neighboring cells. The thickness of this vascular basement membrane was remarkably consistent depending on its location, but never strayed beyond a range of 150–300 nm unless thinned to facilitate closer proximity of neighboring cells (suggesting direct contact). The density of PC-EC contact points (“peg-and-socket” structures) was another distinguishing feature across the different PC subtypes, as were the apparent contact locations between vascular cells and brain parenchymal cells. In addition to this thinning, the extracellular matrix (ECM) surrounding EPs displayed another unique configuration in the form of extensions that emitted out radially into the surrounding parenchyma. Knowledge of the origin and function of these structures is still emerging, but their appearance suggests the potential for being mechanical elements and/or perhaps signaling nodes via embedded molecular cues. Overall, this unique ultrastructural perspective provides new insights into PC heterogeneity and the presence of medial cells within the microvessel wall, the consideration of extracellular matrix (ECM) coverage as another PC identification criteria, and unique extracellular matrix (ECM) configurations (i.e., radial extensions) that may reveal additional aspects of PC heterogeneity.
- Region- and Cell-Specific Expression of Transmembrane Collagens in Mouse BrainMonavarfeshani, Aboozar; Kill, Courtney N.; Sabbagh, Ubadah; Su, Jianmin; Fox, Michael A. (Frontiers, 2017-08-30)Unconventional collagens are nonfribrillar proteins that not only contribute to the structure of extracellular matrices but exhibit unique bio-activities. Although roles for unconventional collagens have been well-established in the development and function of non-neural tissues, only recently have studies identified roles for these proteins in brain development, and more specifically, in the formation and refinement of synaptic connections between neurons. Still, our understanding of the full cohort of unconventional collagens that are generated in the mammalian brain remains unclear. Here, we sought to address this gap by assessing the expression of transmembrane collagens (i.e., collagens XIII, XVII, XXIII and XXV) in mouse brain. Using quantitative PCR and in situ hybridization (ISH), we demonstrate both region- and cell-specific expression of these unique collagens in the developing brain. For the two most highly expressed transmembrane collagens (i.e., collagen XXIII and XXV), we demonstrate that they are expressed by select subsets of neurons in different parts of the brain. For example, collagen XXIII is selectively expressed by excitatory neurons in the mitral/tufted cell layer of the accessory olfactory bulb (AOB) and by cells in the inner nuclear layer (INL) of the retina. On the other hand, collagen XXV, which is more broadly expressed, is generated by subsets of excitatory neurons in the dorsal thalamus and midbrain and by inhibitory neurons in the retina, ventral thalamus and telencephalon. Not only is col25a1 expression present in retina, it appears specifically enriched in retino-recipient nuclei within the brain (including the suprachiasmatic nucleus (SCN), lateral geniculate complex, olivary pretectal nucleus (OPN) and superior colliculus). Taken together, the distinct region- and cell-specific expression patterns of transmembrane collagens suggest that this family of unconventional collagens may play unique, yet-to-be identified roles in brain development and function.
- Retinal inputs signal astrocytes to recruit interneurons into visual thalamusSu, Jianmin; Charalambakis, Naomi E.; Sabbagh, Ubadah; Somaiya, Rachana D.; Monavarfeshani, Aboozar; Guido, William; Fox, Michael A. (2020-02-04)Inhibitory interneurons comprise a fraction of the total neurons in the visual thalamus but are essential for sharpening receptive field properties and improving contrast-gain of retinogeniculate transmission. During early development, these interneurons undergo long-range migration from germinal zones, a process regulated by the innervation of the visual thalamus by retinal ganglion cells. Here, using transcriptomic approaches, we identified a motogenic cue, fibroblast growth factor 15 (FGF15), whose expression in the visual thalamus is regulated by retinal input. Targeted deletion of functional FGF15 in mice led to a reduction in thalamic GABAergic interneurons similar to that observed in the absence of retinal input. This loss may be attributed, at least in part, to misrouting of interneurons into nonvisual thalamic nuclei. Unexpectedly, expression analysis revealed that FGF15 is generated by thalamic astrocytes and not retino-recipient neurons. Thus, these data show that retinal inputs signal through astrocytes to direct the long-range recruitment of interneurons into the visual thalamus.
- Retinal-input-induced epigenetic dynamics in the developing mouse dorsal lateral geniculate nucleusHe, Jianlin; Xu, Xiguang; Monavarfeshani, Aboozar; Banerjee, Sharmi; Fox, Michael A.; Xie, Hehuang David (2019-02-14)DNA methylation plays important roles in the regulation of nervous system development and in cellular responses to environmental stimuli such as light-derived signals. Despite great efforts in understanding the maturation and refinement of visual circuits, we lack a clear understanding of how changes in DNA methylation correlate with visual activity in the developing subcortical visual system, such as in the dorsal lateral geniculate nucleus (dLGN), the main retino-recipient region in the dorsal thalamus. Here, we explored epigenetic dynamics underlying dLGN development at ages before and after eye opening in wild-type mice and mutant mice in which retinal ganglion cells fail to form. We observed that development-related epigenetic changes tend to co-localize together on functional genomic regions critical for regulating gene expression, while retinal-input-induced epigenetic changes are enriched on repetitive elements. Enhancers identified in neurons are prone to methylation dynamics during development, and activity-induced enhancers are associated with retinal-input-induced epigenetic changes. Intriguingly, the binding motifs of activity-dependent transcription factors, including EGR1 and members of MEF2 family, are enriched in the genomic regions with epigenetic aberrations in dLGN tissues of mutant mice lacking retinal inputs. Overall, our study sheds new light on the epigenetic regulatory mechanisms underlying the role of retinal inputs on the development of mouse dLGN.