Martin Bohlen - Academia.edu (original) (raw)
Papers by Martin Bohlen
This study analyzes the light emission pattern of tapered optical fibers (TFs) across different n... more This study analyzes the light emission pattern of tapered optical fibers (TFs) across different numerical apertures (NA), core diameters, laser input powers, cone angles, and light injection angles. The results will be used to tailor optical fibers for optimal light delivery to photosensitive neuronal actuators in the non-human primate (NHP) brain.
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Visual Neuroscience, 2021
A projection by the superior colliculus to the supraoculomotor area (SOA) located dorsal to the o... more A projection by the superior colliculus to the supraoculomotor area (SOA) located dorsal to the oculomotor complex was first described in 1978. This projection’s targets have yet to be identified, although the initial study suggested that vertical gaze motoneuron dendrites might receive this input. Defining the tectal targets is complicated by the fact the SOA contains a number of different cell populations. In the present study, we used anterograde tracers to characterize collicular axonal arbors and retrograde tracers to label prospective SOA target populations in macaque monkeys. Close associations were not found with either superior or medial rectus motoneurons whose axons supply singly innervated muscle fibers. S-group motoneurons, which supply superior rectus multiply innervated muscle fibers, appeared to receive a very minor input, but C-group motoneurons, which supply medial rectus multiply innervated muscle fibers, received no input. A number of labeled boutons were observe...
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Visual Neuroscience, 2021
Since most gaze shifts are to targets that lie at a different distance from the viewer than the c... more Since most gaze shifts are to targets that lie at a different distance from the viewer than the current target, gaze changes commonly require a change in the angle between the eyes. As part of this response, lens curvature must also be adjusted with respect to target distance by the ciliary muscle. It has been suggested that projections by the cerebellar fastigial and posterior interposed nuclei to the supraoculomotor area (SOA), which lies immediately dorsal to the oculomotor nucleus and contains near response neurons, support this behavior. However, the SOA also contains motoneurons that supply multiply innervated muscle fibers (MIFs) and the dendrites of levator palpebrae superioris motoneurons. To better determine the targets of the fastigial nucleus in the SOA, we placed an anterograde tracer into this cerebellar nucleus in Macaca fascicularis monkeys and a retrograde tracer into their contralateral medial rectus, superior rectus, and levator palpebrae muscles. We only observed...
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Human Gene Therapy, 2020
Recently, we established an AAV9 capsid-promoter interaction that directly determined cell-specif... more Recently, we established an AAV9 capsid-promoter interaction that directly determined cell-specific gene expression across two synthetic promoters, Cbh and CBA, in the rat striatum. The present studies not only expand this capsid-promoter interaction to include another promoter in the rat striatum, but also establishes AAV capsid-promoter interactions in the non-human primate brain. When AAV9 vectors were injected into the rat striatum, the minimal synthetic promoter JetI drove GFP gene expression predominantly in oligodendrocytes. However, similar to our previous findings, the insertion of 6 alanines into VP1/VP2 of the AAV9 capsid (AAV9AU) significantly shifted JetI-driven GFP gene expression to neurons. In addition, previous retrograde tracing studies in the non-human primate brain also revealed the existence of a capsid-promoter interaction. When rAAV2-Retro vectors were infused into the frontal eye field (FEF) of rhesus macaques, local gene expression was prominent using either the hybrid chicken beta actin (CAG) or human synapsin (hSyn) promoters. However, only the CAG promoter, not the hSyn promoter, led to gene expression in the ipsilateral claustrum and contralateral FEF. Conversely, infusion of rAAV2-retro-hSyn vectors, but not rAAV2-retro-CAG, into the macaque superior colliculus led to differential and selective retrograde gene expression in cerebellotectal afferent cells. Clearly, this differential promoter/capsid expression profile could not be attributed to promoter inactivation from retrograde transport of the rAAV2-Retro vector. In summary, we document the potential for AAV capsid/promoter interactions to impact cell specific gene expression across species, experimental manipulations and engineered capsids, independent of capsid permissivity.
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Neuron, 2020
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Frontiers in Neuroanatomy, 2019
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Journal of Comparative Psychology, 2019
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The Anatomical Record, 2019
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Molecular and Cellular Endocrinology, 2017
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The Journal of comparative neurology, Jan 2, 2016
In this study, two points related to the pattern of innervation of the extraocular muscles were e... more In this study, two points related to the pattern of innervation of the extraocular muscles were explored. 1. Species differences exist in the location of the motoneurons supplying multiply innervated fibers (MIFs) and singly innervated fibers (SIFs) in eye muscles. MIF motoneurons are located outside the extraocular nuclei in primates, but are intermixed with SIF motoneurons within rat extraocular nuclei. To test whether this difference is related to visual capacity and frontal placement of eyes, we injected retrograde tracers into the medial rectus muscle of the cat, a highly visual, non-primate with frontally placed eyes. Distal injections labeled smaller MIF motoneurons located ventrolaterally and rostrally within the oculomotor nucleus (III). More central injections also labeled a separate population of larger cells, located dorsally in III. Thus, the cat shares the feature of having MIF motoneurons located within the bounds of III with the nocturnal rat. On the other hand, like...
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Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus, 2016
Extraocular proprioception has been shown to participate in spatial perception and binocular alig... more Extraocular proprioception has been shown to participate in spatial perception and binocular alignment. Yet the physiological approaches used to study this sensory signal are limited because proprioceptive signaling takes place at the same time as visuomotor signaling. It is critical to dissociate this sensory signal from other visuomotor events that accompany eye movements. We present a novel noninvasive and quantifiable method for probing extraocular proprioception independent of other visuomotor processing by attaching a rare-earth magnet to a real-time model eye and placing an electromagnet <20 mm from the eye. An electromagnet can increase or decrease angular displacements and velocities of the model eye. Electromagnetic activation rapidly affected (<2 ms) the rotation kinematics of the eye, which were correlated linearly with both the current supply and the distance of the electromagnet relative to the eye. This method circumvented the constraints of conventional physiol...
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Physiology & behavior, Jan 11, 2015
Exposure to unpredictable chronic mild stress (CUS) is a commonly used protocol in rats that is r... more Exposure to unpredictable chronic mild stress (CUS) is a commonly used protocol in rats that is reported to evoke antidepressant-reversible behaviors such as loss of preference for sweetened water solution which is taken as an analog of the anhedonia seen in major depression. However, the induction of anhedonic-like behavior by chronic mild stress, gauged by an animal's preference for sucrose solution, is not fully reproducible and consistent across laboratories. In this study, we compared a widely used behavioral marker of anhedonia - the sucrose preference test, with another phenotypic marker of emotional valence, social interaction-associated ultrasonic vocalizations as well as a marker of an anxiety-like phenotype, novelty-suppressed feeding, and cognitive performance in the eight arm radial maze task in adult male Sprague-Dawley rats. Chronic four-week exposure to unpredictable mild stressors resulted in 1) attenuation of social interaction-associated ultrasonic vocalizatio...
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Journal of Neuroscience Methods, 2020
BACKGROUND Recent genetic technologies such as opto- and chemogenetics allow for the manipulation... more BACKGROUND Recent genetic technologies such as opto- and chemogenetics allow for the manipulation of brain circuits with unprecedented precision. Most studies employing these techniques have been undertaken in rodents, but a more human-homologous model for studying the brain is the nonhuman primate (NHP). Optimizing viral delivery of transgenes encoding actuator proteins could revolutionize the way we study neuronal circuits in NHPs. NEW METHOD: rAAV2-retro, a popular new capsid variant, produces robust retrograde labeling in rodents. Whether rAAV2-retro's highly efficient retrograde transport would translate to NHPs was unknown. Here, we characterized the anatomical distribution of labeling following injections of rAAV2-retro encoding opsins or DREADDs in the cortico-basal ganglia and oculomotor circuits of rhesus macaques. RESULTS rAAV2-retro injections in striatum, frontal eye field, and superior colliculus produced local labeling at injection sites and robust retrograde labeling in many afferent regions. In every case, however, a few brain regions with well-established projections to the injected structure lacked retrogradely labeled cells. We also observed robust terminal field labeling in downstream structures. COMPARISON WITH EXISTING METHOD(S) Patterns of labeling were similar to those obtained with traditional tract-tracers, except for some afferent labeling that was noticeably absent. CONCLUSIONS rAAV2-retro promises to be useful for circuit manipulation via retrograde transduction in NHPs, but caveats were revealed by our findings. Some afferently connected regions lacked retrogradely labeled cells, showed robust axon terminal labeling, or both. This highlights the importance of anatomically characterizing rAAV2-retro's expression in target circuits in NHPs before moving to manipulation studies.
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Behav Brain Res., 2014
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Journal of Neuroscience Methods, 2009
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Genes, Brain and Behavior, 2012
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Brain structure & function, Jan 10, 2015
The central mesencephalic reticular formation is physiologically implicated in oculomotor functio... more The central mesencephalic reticular formation is physiologically implicated in oculomotor function and anatomically interwoven with many parts of the oculomotor system's premotor circuitry. This study in Macaca fascicularis monkeys investigates the pattern of central mesencephalic reticular formation projections to the area in and around the extraocular motor nuclei, with special emphasis on the supraoculomotor area. It also examines the location of the cells responsible for this projection. Injections of biotinylated dextran amine were stereotaxically placed within the central mesencephalic reticular formation to anterogradely label axons and terminals. These revealed bilateral terminal fields in the supraoculomotor area. In addition, dense terminations were found in both the preganglionic Edinger-Westphal nuclei. The dense terminations just dorsal to the oculomotor nucleus overlap with the location of the C-group medial rectus motoneurons projecting to multiply innervated musc...
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Behav Brain Res., 2014
Bookmarks Related papers MentionsView impact
Journal of Neuroscience Methods, 2009
Bookmarks Related papers MentionsView impact
Journal of Neuroscience Methods, 2010
Bookmarks Related papers MentionsView impact
This study analyzes the light emission pattern of tapered optical fibers (TFs) across different n... more This study analyzes the light emission pattern of tapered optical fibers (TFs) across different numerical apertures (NA), core diameters, laser input powers, cone angles, and light injection angles. The results will be used to tailor optical fibers for optimal light delivery to photosensitive neuronal actuators in the non-human primate (NHP) brain.
Bookmarks Related papers MentionsView impact
Visual Neuroscience, 2021
A projection by the superior colliculus to the supraoculomotor area (SOA) located dorsal to the o... more A projection by the superior colliculus to the supraoculomotor area (SOA) located dorsal to the oculomotor complex was first described in 1978. This projection’s targets have yet to be identified, although the initial study suggested that vertical gaze motoneuron dendrites might receive this input. Defining the tectal targets is complicated by the fact the SOA contains a number of different cell populations. In the present study, we used anterograde tracers to characterize collicular axonal arbors and retrograde tracers to label prospective SOA target populations in macaque monkeys. Close associations were not found with either superior or medial rectus motoneurons whose axons supply singly innervated muscle fibers. S-group motoneurons, which supply superior rectus multiply innervated muscle fibers, appeared to receive a very minor input, but C-group motoneurons, which supply medial rectus multiply innervated muscle fibers, received no input. A number of labeled boutons were observe...
Bookmarks Related papers MentionsView impact
Visual Neuroscience, 2021
Since most gaze shifts are to targets that lie at a different distance from the viewer than the c... more Since most gaze shifts are to targets that lie at a different distance from the viewer than the current target, gaze changes commonly require a change in the angle between the eyes. As part of this response, lens curvature must also be adjusted with respect to target distance by the ciliary muscle. It has been suggested that projections by the cerebellar fastigial and posterior interposed nuclei to the supraoculomotor area (SOA), which lies immediately dorsal to the oculomotor nucleus and contains near response neurons, support this behavior. However, the SOA also contains motoneurons that supply multiply innervated muscle fibers (MIFs) and the dendrites of levator palpebrae superioris motoneurons. To better determine the targets of the fastigial nucleus in the SOA, we placed an anterograde tracer into this cerebellar nucleus in Macaca fascicularis monkeys and a retrograde tracer into their contralateral medial rectus, superior rectus, and levator palpebrae muscles. We only observed...
Bookmarks Related papers MentionsView impact
Human Gene Therapy, 2020
Recently, we established an AAV9 capsid-promoter interaction that directly determined cell-specif... more Recently, we established an AAV9 capsid-promoter interaction that directly determined cell-specific gene expression across two synthetic promoters, Cbh and CBA, in the rat striatum. The present studies not only expand this capsid-promoter interaction to include another promoter in the rat striatum, but also establishes AAV capsid-promoter interactions in the non-human primate brain. When AAV9 vectors were injected into the rat striatum, the minimal synthetic promoter JetI drove GFP gene expression predominantly in oligodendrocytes. However, similar to our previous findings, the insertion of 6 alanines into VP1/VP2 of the AAV9 capsid (AAV9AU) significantly shifted JetI-driven GFP gene expression to neurons. In addition, previous retrograde tracing studies in the non-human primate brain also revealed the existence of a capsid-promoter interaction. When rAAV2-Retro vectors were infused into the frontal eye field (FEF) of rhesus macaques, local gene expression was prominent using either the hybrid chicken beta actin (CAG) or human synapsin (hSyn) promoters. However, only the CAG promoter, not the hSyn promoter, led to gene expression in the ipsilateral claustrum and contralateral FEF. Conversely, infusion of rAAV2-retro-hSyn vectors, but not rAAV2-retro-CAG, into the macaque superior colliculus led to differential and selective retrograde gene expression in cerebellotectal afferent cells. Clearly, this differential promoter/capsid expression profile could not be attributed to promoter inactivation from retrograde transport of the rAAV2-Retro vector. In summary, we document the potential for AAV capsid/promoter interactions to impact cell specific gene expression across species, experimental manipulations and engineered capsids, independent of capsid permissivity.
Bookmarks Related papers MentionsView impact
Neuron, 2020
Bookmarks Related papers MentionsView impact
Frontiers in Neuroanatomy, 2019
Bookmarks Related papers MentionsView impact
Journal of Comparative Psychology, 2019
Bookmarks Related papers MentionsView impact
The Anatomical Record, 2019
Bookmarks Related papers MentionsView impact
Molecular and Cellular Endocrinology, 2017
Bookmarks Related papers MentionsView impact
The Journal of comparative neurology, Jan 2, 2016
In this study, two points related to the pattern of innervation of the extraocular muscles were e... more In this study, two points related to the pattern of innervation of the extraocular muscles were explored. 1. Species differences exist in the location of the motoneurons supplying multiply innervated fibers (MIFs) and singly innervated fibers (SIFs) in eye muscles. MIF motoneurons are located outside the extraocular nuclei in primates, but are intermixed with SIF motoneurons within rat extraocular nuclei. To test whether this difference is related to visual capacity and frontal placement of eyes, we injected retrograde tracers into the medial rectus muscle of the cat, a highly visual, non-primate with frontally placed eyes. Distal injections labeled smaller MIF motoneurons located ventrolaterally and rostrally within the oculomotor nucleus (III). More central injections also labeled a separate population of larger cells, located dorsally in III. Thus, the cat shares the feature of having MIF motoneurons located within the bounds of III with the nocturnal rat. On the other hand, like...
Bookmarks Related papers MentionsView impact
Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus, 2016
Extraocular proprioception has been shown to participate in spatial perception and binocular alig... more Extraocular proprioception has been shown to participate in spatial perception and binocular alignment. Yet the physiological approaches used to study this sensory signal are limited because proprioceptive signaling takes place at the same time as visuomotor signaling. It is critical to dissociate this sensory signal from other visuomotor events that accompany eye movements. We present a novel noninvasive and quantifiable method for probing extraocular proprioception independent of other visuomotor processing by attaching a rare-earth magnet to a real-time model eye and placing an electromagnet <20 mm from the eye. An electromagnet can increase or decrease angular displacements and velocities of the model eye. Electromagnetic activation rapidly affected (<2 ms) the rotation kinematics of the eye, which were correlated linearly with both the current supply and the distance of the electromagnet relative to the eye. This method circumvented the constraints of conventional physiol...
Bookmarks Related papers MentionsView impact
Physiology & behavior, Jan 11, 2015
Exposure to unpredictable chronic mild stress (CUS) is a commonly used protocol in rats that is r... more Exposure to unpredictable chronic mild stress (CUS) is a commonly used protocol in rats that is reported to evoke antidepressant-reversible behaviors such as loss of preference for sweetened water solution which is taken as an analog of the anhedonia seen in major depression. However, the induction of anhedonic-like behavior by chronic mild stress, gauged by an animal's preference for sucrose solution, is not fully reproducible and consistent across laboratories. In this study, we compared a widely used behavioral marker of anhedonia - the sucrose preference test, with another phenotypic marker of emotional valence, social interaction-associated ultrasonic vocalizations as well as a marker of an anxiety-like phenotype, novelty-suppressed feeding, and cognitive performance in the eight arm radial maze task in adult male Sprague-Dawley rats. Chronic four-week exposure to unpredictable mild stressors resulted in 1) attenuation of social interaction-associated ultrasonic vocalizatio...
Bookmarks Related papers MentionsView impact
Journal of Neuroscience Methods, 2020
BACKGROUND Recent genetic technologies such as opto- and chemogenetics allow for the manipulation... more BACKGROUND Recent genetic technologies such as opto- and chemogenetics allow for the manipulation of brain circuits with unprecedented precision. Most studies employing these techniques have been undertaken in rodents, but a more human-homologous model for studying the brain is the nonhuman primate (NHP). Optimizing viral delivery of transgenes encoding actuator proteins could revolutionize the way we study neuronal circuits in NHPs. NEW METHOD: rAAV2-retro, a popular new capsid variant, produces robust retrograde labeling in rodents. Whether rAAV2-retro's highly efficient retrograde transport would translate to NHPs was unknown. Here, we characterized the anatomical distribution of labeling following injections of rAAV2-retro encoding opsins or DREADDs in the cortico-basal ganglia and oculomotor circuits of rhesus macaques. RESULTS rAAV2-retro injections in striatum, frontal eye field, and superior colliculus produced local labeling at injection sites and robust retrograde labeling in many afferent regions. In every case, however, a few brain regions with well-established projections to the injected structure lacked retrogradely labeled cells. We also observed robust terminal field labeling in downstream structures. COMPARISON WITH EXISTING METHOD(S) Patterns of labeling were similar to those obtained with traditional tract-tracers, except for some afferent labeling that was noticeably absent. CONCLUSIONS rAAV2-retro promises to be useful for circuit manipulation via retrograde transduction in NHPs, but caveats were revealed by our findings. Some afferently connected regions lacked retrogradely labeled cells, showed robust axon terminal labeling, or both. This highlights the importance of anatomically characterizing rAAV2-retro's expression in target circuits in NHPs before moving to manipulation studies.
Bookmarks Related papers MentionsView impact
Behav Brain Res., 2014
Bookmarks Related papers MentionsView impact
Journal of Neuroscience Methods, 2009
Bookmarks Related papers MentionsView impact
Genes, Brain and Behavior, 2012
Bookmarks Related papers MentionsView impact
Brain structure & function, Jan 10, 2015
The central mesencephalic reticular formation is physiologically implicated in oculomotor functio... more The central mesencephalic reticular formation is physiologically implicated in oculomotor function and anatomically interwoven with many parts of the oculomotor system's premotor circuitry. This study in Macaca fascicularis monkeys investigates the pattern of central mesencephalic reticular formation projections to the area in and around the extraocular motor nuclei, with special emphasis on the supraoculomotor area. It also examines the location of the cells responsible for this projection. Injections of biotinylated dextran amine were stereotaxically placed within the central mesencephalic reticular formation to anterogradely label axons and terminals. These revealed bilateral terminal fields in the supraoculomotor area. In addition, dense terminations were found in both the preganglionic Edinger-Westphal nuclei. The dense terminations just dorsal to the oculomotor nucleus overlap with the location of the C-group medial rectus motoneurons projecting to multiply innervated musc...
Bookmarks Related papers MentionsView impact
Behav Brain Res., 2014
Bookmarks Related papers MentionsView impact
Journal of Neuroscience Methods, 2009
Bookmarks Related papers MentionsView impact
Journal of Neuroscience Methods, 2010
Bookmarks Related papers MentionsView impact