About

Martha M. Bosma is a professor in the Department of Biology at the University of Washington. Her research focuses on the early development of the brainstem region, which becomes the pons, medulla, midbrain, and cerebellum. She studies the physiological and morphological aspects of serotonergic (5HT) neurons, which in the adult brain regulate mood, sleep, and behavior. Her work investigates how spontaneous waves occur in the developing hindbrain that require serotonergic receptor signaling, and how modulation of this signaling alters the expression of the serotonergic phenotype. Using techniques such as intracellular calcium imaging, patch clamp, immunocytochemistry, and tissue culture, she explores the functional development of serotonergic neurons in wildtype and transgenic animals. Her research has shown that over short developmental periods, the expression of voltage-gated ion channels and the propagation of spontaneous activity waves change dramatically, and she is interested in how these changes influence the development of neuromodulatory neurons in the brainstem.

Research topics

• Computer Science
• Cell biology
• Anatomy
• Neuroscience
• Biology
• Materials science
• Internal medicine
• Medicine
• Biological system

Selected publications

• A complete biomechanical model of <i>Hydra</i> contractile behaviors, from neural drive to muscle to movement

  Proceedings of the National Academy of Sciences · 2023 · 39 citations

  • Computer Science
  • Neuroscience
  • Anatomy

  movement and can serve as a template for future efforts to systematically decipher the transformations in the neural basis of behavior.

  PublisherOA PDFDOI

• Rode urine na het wandelen: 2 casusbeschrijvingen

  Laboratoriumgeneeskunde · 2021

  1st authorCorresponding
  • Medicine
  • Internal medicine
  PublisherDOI

• From neuron to muscle to movement: a complete biomechanical model of <i>Hydra</i> contractile behaviors

  bioRxiv (Cold Spring Harbor Laboratory) · 2020 · 9 citations

  • Computer Science
  • Neuroscience
  • Anatomy

  Abstract How does neural activity drive muscles to produce behavior? The recent development of genetic lines in Hydra that allow complete calcium imaging of both neuronal and muscle activity, as well as systematic machine learning quantification of behaviors, makes this small Cnidarian an ideal model system to understand and model the complete transformation from neural firing to body movements. As a first step to achieve this, we have built a biomechanical model of Hydra , incorporating its neuronal activity, muscle activity and body column biomechanics, incorporating its fluid-filled hydrostatic skeleton. Our model is based on experimental measurements of neuronal and muscle activity, and assumes gap junctional coupling among muscle cells and calcium-dependent force generation y muscles. With these assumptions, we can robustly reproduce a basic set of Hydra’s behaviors. We can further explain puzzling experimental observations, including the dual kinetics observed in muscle activation and the different engagement of ecto- and endodermal muscle in different behaviors. This work delineates the spatiotemporal control space of Hydra movement and can serve as a template for future efforts to systematically decipher the transformations in the neural basis of behavior.

  PublisherOA PDFDOI

• Regulation of Spontaneous Propagating Waves in the Embryonic Mouse Brainstem

  Frontiers in Neural Circuits · 2017-01-04 · 1 citations

  articleOpen access1st authorCorresponding

  Spontaneous activity modulates many aspects of neural development, including neuronal phenotype, axon path-finding and synaptic connectivity. In the embryonic mouse brainstem, spontaneous activity initially is recorded in isolated cells at embryonic day (E) 9.5, and 48 hours later takes the form of propagating waves. The majority of these waves originate from one midline initiation zone (InZ), which is situated within the developing serotonergic raphe. InZ cells express a t-type calcium channel, are depolarized, and have high membrane resistance, the combination of which allows spontaneous depolarization. Propagating events require signaling at metabotropic 5-HT receptors; a possible source could be 5-HT released by newly differentiating 5-HT neurons. At E11.5, waves propagate throughout the hindbrain, with some events crossing into the midbrain. At E12.5, lateral cells (further than 150 μm from the midline) up-regulate expression of a K channel that increases resting conductance and hyperpolarizes them, preventing the propagation of waves laterally. At the same stage, cells in the isthmus up-regulate t-type calcium channels, permitting more events to cross into the midbrain, some of which form recurring loops of activity that are able to keep intracellular calcium levels high for many minutes. At E13.5, caudal hindbrain cells hyperpolarize utilizing the same K conductance, and 24 hours later, at E14.5, the InZ hyperpolarizes and no longer undergoes spontaneous events. Thus, 5-HT receptor-dependent propagating waves in the embryonic brainstem are generated and propagated by regulation of membrane conductance. We discuss these mechanisms, and the possible role of this spontaneous activity in neuronal development.

  PublisherOA PDFDOI

• Looping circuit: a novel mechanism for prolonged spontaneous [Ca²⁺]_i increases in developing embryonic mouse brainstem

  The Journal of Physiology · 2013-12-24 · 5 citations

  articleOpen accessSenior authorCorresponding

  Key points Calcium concentration is kept at extremely low levels inside brain cells; each episode of calcium entry is cleared within seconds. Changes in calcium entry are mediated by spontaneous activity in embryonic mouse brainstem from embryonic day 11.5 to 13.5. Transiently, at embryonic day 12.5, spontaneous events occur frequently such that calcium concentration stays above baseline levels for minutes. This unusual phenomenon, which we termed ‘bash bursts’, is caused by an event that propagates by looping along a defined path; the path gets modified a day later, ending it. The results help us to understand how prolonged increases in calcium concentration can occur in development and how the increases may influence the development of serotonin and dopamine circuits that are related to neurological diseases later in life, such as depression and Parkinson's disease. Abstract Most cells maintain [Ca 2+ ] i at extremely low levels; calcium entry usually occurs briefly, and within seconds it is cleared. However, at embryonic day 12.5 in the mouse brainstem, trains of spontaneous events occur with [Ca 2+ ] i staying close to peak value, well above baseline, for minutes; we termed this ‘bash bursts’. Here, we investigate the mechanism of this unusual activity using calcium imaging and electrophysiology. Bash bursts are triggered by an event originating at the mid‐line of the rostral hindbrain and are usually the result of that event propagating repeatedly along a defined circular path. The looping circuit can either encompass both the midbrain and hindbrain or remain in the hindbrain only, and the type of loop determines the duration of a single lap time, 5 or 3 s, respectively. Bash bursts are supported by high membrane excitability of mid‐line cells and are regulated by persistent inward ‘window current’ at rest, contributing to spontaneous activity. This looping circuit is an effective means for increasing [Ca 2+ ] i at brief, regular intervals. Bash bursts disappear by embryonic day 13.5 via alteration of the looping circuit, curtailing the short epoch of bash bursts. The resulting sustained [Ca 2+ ] i may influence development of raphe serotonergic and ventral tegmental dopaminergic neurons by modulating gene expression.

  PublisherOA PDFDOI

• Hyperpolarization of resting membrane potential causes retraction of spontaneous transients during mouse embryonic circuit development

  The Journal of Physiology · 2012-11-20 · 7 citations

  articleOpen accessSenior author

  Key points A wave of electrical activity occurs in the developing brain for a certain period of time before sensory, motor and cognitive functions mature. This electrical activity, or spontaneous activity, originates, spreads, then later retracts and disappears in specific areas of the brain at specific time points, but how it retracts is unknown. We report that retraction in the mouse embryonic hindbrain is caused by a reduced excitability in the network of cells. This process can be reversed by bath application of high K + solution, which increases excitability. This reduced excitability is probably caused by increased number of K + pores that are always open in individual cells. These results help us understand how the spread of spontaneous activity is regulated and ultimately help us better understand the role of electrical activity during development of the fetal brain. Abstract Spontaneous activity supports developmental processes in many brain regions during embryogenesis, and the spatial extent and frequency of the spontaneous activity are tightly regulated by stage. In the developing mouse hindbrain, spontaneous activity propagates widely and the waves can cover the entire hindbrain at E11.5. The activity then retracts to waves that are spatially restricted to the rostral midline at E13.5, before disappearing altogether by E15.5. However, the mechanism of retraction is unknown. We studied passive membrane properties of cells that are spatiotemporally relevant to the pattern of retraction in mouse embryonic hindbrain using whole‐cell patch clamp and imaging techniques. We find that membrane excitability progressively decreases due to hyperpolarization of resting membrane potential and increased resting conductance density between E11.5 and E15.5, in a spatiotemporal pattern correlated with the retraction sequence. Retraction can be acutely reversed by membrane depolarization at E15.5, and the induced events propagate similarly to spontaneous activity at earlier stages, though without involving gap junctional coupling. Manipulation of [K + ] o or [Cl − ] o reveals that membrane potential follows E K more closely than E Cl , suggesting a dominant role for K + conductance in the membrane hyperpolarization. Reducing membrane excitability by hyperpolarization of the resting membrane potential and increasing resting conductance are effective mechanisms to desynchronize spontaneous activity in a spatiotemporal manner, while allowing information processing to occur at the synaptic and cellular level.

  PublisherOA PDFDOI

• Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

  Proceedings of the National Academy of Sciences · 2012-01-05 · 101 citations

  article

  Na(V)1.1 is the primary voltage-gated Na(+) channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that Na(V)1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a(+/-)), which encodes the pore-forming α-subunit of the Na(V)1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a(+/-) mice have exaggerated light-induced negative-masking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a(+/-) mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a(+/-) mice, and this communication is barely detectable in the homozygous gene KO (Scn1a(-/-)). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of Na(V)1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na(+) channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of Na(V)1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients.

  PublisherDOI

• Timing and mechanism of a window of spontaneous activity in embryonic mouse hindbrain development

  Annals of the New York Academy of Sciences · 2010-06-01 · 13 citations

  article1st authorCorresponding

  Spontaneous activity (SA) in the developing vertebrate brain is required for correct wiring of circuits and networks. In almost every brain region studied to date, SA is recorded during a period of synaptogenesis, and may deploy ionic mechanism(s) that are not expressed in the adult structure. Eventually the conditions in the immature neurons that allow SA are replaced with ion channels found in the mature neuron; this replacement may itself require SA. In the embryonic (E) 11.5 mouse hindbrain, SA is initiated by a subgroup of serotonergic neurons derived from former rhombomeres 2 and 3; SA events propagate rostrally and caudally along the midline, and into the lateral hindbrain. In this review, I describe the properties of mouse hindbrain SA and the developmental window during which it is expressed, summarize the known mechanisms by which SA arises, and describe other brain regions where this SA is similar (chick hindbrain) or influential (mouse midbrain).

  PublisherDOI

• Differential expression of membrane conductances underlies spontaneous event initiation by rostral midline neurons in the embryonic mouse hindbrain

  The Journal of Physiology · 2009-09-08 · 14 citations

  articleOpen accessSenior author

  Spontaneous activity is expressed in many developing CNS structures and is crucial in correct network development. Previous work using [Ca(2+)](i) imaging showed that in the embryonic mouse hindbrain spontaneous activity is initiated by a driver population, the serotonergic neurons of the nascent raphe. Serotonergic neurons derived from former rhombomere 2 drive 90% of all hindbrain events at E11.5. We now demonstrate that the electrical correlate of individual events is a spontaneous depolarization, which originates at the rostral midline and drives events laterally. Midline events have both a rapid spike and a large plateau component, while events in lateral tissue comprise only a smaller amplitude plateau. Lateral cells have a large resting conductance and are highly coupled via neurobiotin-permeant gap junctions, while midline cells are significantly less gap junction-coupled and uniquely express a T-type Ca(2+) channel. We propose that the combination of low resting conductance and expression of T-type Ca(2+) current is permissive for midline neurons to acquire the initiator or driver phenotype, while cells without these features cannot drive activity. This demonstrates that expression of specific conductances contributes to the ability to drive spontaneous activity in a developing network.

  PublisherOA PDFDOI

• Spontaneous activity in the developing mouse midbrain driven by an external pacemaker

  Developmental Neurobiology · 2009-05-15 · 20 citations

  articleSenior authorCorresponding

  Central nervous system (CNS) development depends upon spontaneous activity (SA) to establish networks. We have discovered that the mouse midbrain has SA expressed most robustly at embryonic day (E) 12.5. SA propagation in the midbrain originates in midline serotonergic cell bodies contained within the adjacent hindbrain and then passes through the isthmus along ventral midline serotonergic axons. Once within the midbrain, the wave bifurcates laterally along the isthmic border and then propagates rostrally. Along this trajectory, it is carried by a combination of GABAergic and cholinergic neurons. Removing the hindbrain eliminates SA in the midbrain. Thus, SA in the embryonic midbrain arises from a single identified pacemaker in a separate brain structure, which drives SA waves across both regions of the developing CNS. The midbrain can self-initiate activity upon removal of the hindbrain, but only with pharmacological manipulations that increase excitability. Under these conditions, new initiation foci within the midbrain become active. Anatomical analysis of the development of the serotonergic axons that carry SA from the hindbrain to the midbrain indicates that their increasing elongation during development may control the onset of SA in the midbrain.

  PublisherDOI

Recent grants

• Mechanism of Spontaneous Activity in Embryonic Mouse Hindbrain

  NSF · $400k · 2006–2010

• Mechanisms of spontaneous activity in embryonic hindbrain pacemaker neurons

  NSF · $529k · 2010–2014

• Activity-dependent mechanisms controlling the developmental timing of spontaneous

  NIH · $256k · 2014–2016

Frequent coauthors

• William J. Moody

  University of Washington

  8 shared

• Vasiliki Demas

  Menlo School

  5 shared

• Linda C. Robinson

  Geriatric Research Education and Clinical Center

  5 shared

• Melissa R. Regan

  Johns Hopkins University

  5 shared

• Bertil Hille

  5 shared

• Bruce L. Tempel

  University of Washington

  5 shared

• William S. Agnew

  Google (United Kingdom)

  5 shared

• William A. Catterall

  University of Washington

  4 shared

Education

• B.S., Neurobiology and Comparative Physiology

  McGill University

• Ph.D., Physiology

  University of California, Los Angeles (UCLA)