Lauren Orefice

Last updated
Lauren Orefice
NationalityAmerican
Alma mater Boston College
Georgetown University
Harvard Medical School
Known forRole of peripheral neuron hyperactivity in ASD symptoms
Awards2019 Eppendorf & Science Prize for Neurobiology, 2018 Regeneron Prize for Creative Innovation, 2016 Notable Papers of 2016 Simons Foundation Spotlight
Scientific career
FieldsNeuroscience
Institutions Harvard Medical School

Lauren Orefice is an American neuroscientist and assistant professor in the Department of Molecular Biology at Massachusetts General Hospital and in the Department of Genetics at Harvard Medical School. Orefice has made innovative discoveries about the role of peripheral nerves and sensory hypersensitivity in the development of Autism-like behaviors. Her research now focuses on exploring the basic biology of somatosensory neural circuits for both touch and gastrointestinal function in order to shed light on how peripheral sensation impacts brain development and susceptibility to diseases like Autism Spectrum Disorders.

Contents

Early life and education

Orefice pursued her undergraduate degree at Boston College. [1] She majored in biology and worked in the lab of Stephen C. Heinrichs. [2] She studied the neurobiological underpinning of seizure susceptibility in mice and published a first author paper in Epilepsy and Behavior. [3] She used mouse models of idiopathic epilepsy (IE) to explore how increased parental investment impacted seizure susceptibility in offspring with IE. [3] She strikingly found that when pups with a genetic susceptibility to seizures are biparentally reared, this decreases the time to first seizure compared to pups that are only reared by a dam. [3] The increased exposure to parenting, by 350% compared to uniparental rearing, was a form of stressor which impacted seizure susceptibility. [3]

After completing her Bachelors of Science, Orefice pursued her graduate work in neuroscience at Georgetown University in 2008. [4] She worked under the mentorship of Baoji Xu studying the role of BDNF in dendritic spine morphogenesis in the hippocampus. [5] Her first paper in the lab highlighted the differential roles of two types of BDNF mRNA in spine growth and maturation. [6] She found a form of BDNF mRNA with a short 3’ untranslated region (UTR) that was present in the soma and promoted spine formation. [6] She also found a second form in the dendrites that is locally translated and has a long 3’ UTR and seems to play a role in promoting spine head growth and pruning. [6] Orefice then further probed how dendritic BDNF exerts its effects on synapse maturation and pruning. [7] She found that neuronal activity promoted the translation of local BDNF mRNA in the dendrites, while translation of BDNF in the soma is independent of action potentials. [7] Further, neuronal activity also promotes the secretion of proBDNF from the dendrite which then effects pruning via binding to the p75NTR receptor. [7] This work fascinatingly highlighted the distinct pathways and translational regulation of somatic versus dendritic BDNF. [7] Orefice completed her graduate training in 2013. [8]

Career and research

In 2014, Orefice pursued her postdoctoral work in the lab of David Ginty at Harvard Medical School. [9] In the Ginty Lab, Orefice studied the peripheral somatosensory system, a substantial change from her prior work in the central nervous system. [5] Orefice reported in an interview with Harvard Medical School that this large field change helped her to see that broad research concepts and skills can easily be transferred between fields and are critical in long-term development as a scientist. [5] During her postdoctoral work, Orefice discovered that dysfunction at the level of peripheral somatosensory neurons accounted for touch over-reactivity in ASD models as well as the development of both social defects and anxiety like behavior. [1] She later targeted hyperactivity of peripheral neurons using an agonist for inhibitory neurons and was able to ameliorate ASD-like behaviors in rodent models of ASD. [10]

In 2019, Orefice was promoted to Assistant Professor in the Department of Molecular Biology at Massachusetts General Hospital as well as assistant professor in the Department of Genetics at Harvard University. [1] She is the principal investigator of the Orefice Lab and her research focuses on understanding the basic biology of the somatosensory circuits that mediate touch and sensations within the gastrointestinal system. [11] She is particularly interested in exploring the development and function of peripheral sensory neurons that innervate internal organs since these might mediate the brain-gut connection to influence behavior and brain-related disease. [11] They further explore how somatosensory processing is aberrant in ASD and how GI dysfunction in ASD might be mediated at the level of the periphery. [11] Lastly, the lab hopes to perform translational work using patient derived iPSCs to move their findings into cellular models and hopefully closer to affecting patients in the clinic. [11]

Peripheral somatosensory neuron dysfunction and autism spectrum disorder

During her postdoctoral work, Orefice made critical discoveries surrounding the role of the peripheral sensory nervous system in the development of autism-like behaviors. [10]  It is known that tactile sensitivity is often aberrant in both humans with autism spectrum disorder (ASD) as well as mouse models of ASD. [12] Orefice sought to understand which somatosensory neural circuits were dysfunctional in ASD mouse models as well as how peripheral somatosensory dysfunction contributes to disordered behavioral phenotypes. [12] She deleted ASD-related genes (MeCP2 and Gabrb3) in peripheral neurons and found that absence of these genes, in peripheral tactile neurons only, during development lead to defects in social interaction and anxiety-like behavior later in life. [12] However, when these genes were deleted in the forebrain or during adulthood, there was no somatosensory over-reactivity. [12]  When MeCP2 was selectively expressed in only the peripheral sensory neurons, this was enough to restore defects in touch sensitivity, social behavior, and anxiety. [12] Overall, her findings pointing to the periphery as the site at which these ASD mutations exert their influence on sensory over-reactivity and its contribution to ASD phenotypes. [12]

Orefice followed these findings to explore the possibility of targeting the peripheral somatosensory neurons therapeutically in ASD models. [13] Since she found that peripheral sensory neuron hyperactivity in development was linked to ASD-like behaviors in adulthood as well as impairments in specific brain circuits, Orefice treated ASD models with peripherally restricted GABAa receptor agonists to increase inhibition at the level of mechanosensory neurons. [13] Peripheral action of this drug led to decreased hypersensitivity and improved some brain circuit dysfunction, anxiety-like behaviors, and social impairments but not the memory and motor defects associated with ASD. [13] Her work points to the potential in modulating peripheral neurons, instead of having to target the brain, as a potential therapy for ASD. [14]

Awards and honors

Select publications

Related Research Articles

<span class="mw-page-title-main">Dendrite</span> Small projection on a neuron that receives signals

A dendrite or dendron is a branched protoplasmic extension of a nerve cell that propagates the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project. Electrical stimulation is transmitted onto dendrites by upstream neurons via synapses which are located at various points throughout the dendritic tree.

<span class="mw-page-title-main">Neuron</span> Electrically excitable cell found in the nervous system of animals

Within a nervous system, a neuron, neurone, or nerve cell is an electrically excitable cell that fires electric signals called action potentials across a neural network. Neurons communicate with other cells via synapses, which are specialized connections that commonly use minute amounts of chemical neurotransmitters to pass the electric signal from the presynaptic neuron to the target cell through the synaptic gap.

<span class="mw-page-title-main">Fragile X syndrome</span> X-linked dominant genetic disorder

Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common, and seizures occur in about 10%. Males are usually more affected than females.

<span class="mw-page-title-main">Dendritic spine</span> Small protrusion on a dendrite that receives input from a single axon

A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head, and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons. It has also been suggested that changes in the activity of neurons have a positive effect on spine morphology.

<span class="mw-page-title-main">Brain-derived neurotrophic factor</span> Protein found in humans

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

<span class="mw-page-title-main">Pyramidal cell</span> Projection neurons in the cerebral cortex and hippocampus

Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal cells are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. One of the main structural features of the pyramidal neuron is the conic shaped soma, or cell body, after which the neuron is named. Other key structural features of the pyramidal cell are a single axon, a large apical dendrite, multiple basal dendrites, and the presence of dendritic spines.

An apical dendrite is a dendrite that emerges from the apex of a pyramidal cell. Apical dendrites are one of two primary categories of dendrites, and they distinguish the pyramidal cells from spiny stellate cells in the cortices. Pyramidal cells are found in the prefrontal cortex, the hippocampus, the entorhinal cortex, the olfactory cortex, and other areas. Dendrite arbors formed by apical dendrites are the means by which synaptic inputs into a cell are integrated. The apical dendrites in these regions contribute significantly to memory, learning, and sensory associations by modulating the excitatory and inhibitory signals received by the pyramidal cells.

A basal dendrite is a dendrite that emerges from the base of a pyramidal cell that receives information from nearby neurons and passes it to the soma, or cell body. Due to their direct attachment to the cell body itself, basal dendrites are able to deliver strong depolarizing currents and therefore have a strong effect on action potential output in neurons. The physical characteristics of basal dendrites vary based on their location and species that they are found in. For example, the basal dendrites of humans are overall found to be the most intricate and spine-dense, as compared to other species such as Macaques. It is also observed that basal dendrites of the prefrontal cortex are larger and more complex in comparison to the smaller and simpler dendrites that can be seen within the visual cortex. Basal dendrites are capable of vast amounts of analog computing, which is responsible for many of the different nonlinear responses of modulating information in the neocortex. Basal dendrites additionally exist in dentate granule cells for a limited time before removal via regulatory factors. This removal usually occurs before the cell reaches adulthood, and is thought to be regulated through both intracellular and extracellular signals. Basal dendrites are part of the more overarching dendritic tree present on pyramidal neurons. They, along with apical dendrites, make up the part of the neuron that receives most of the electrical signaling. Basal dendrites have been found to be involved mostly in neocortical information processing.

<span class="mw-page-title-main">Stellate cell</span>

Stellate cells are neurons in the central nervous system, named for their star-like shape formed by dendritic processes radiating from the cell body. Many stellate cells are GABAergic and are located in the molecular layer of the cerebellum. Stellate cells are derived from dividing progenitor cells in the white matter of postnatal cerebellum. Dendritic trees can vary between neurons. There are two types of dendritic trees in the cerebral cortex, which include pyramidal cells, which are pyramid shaped and stellate cells which are star shaped. Dendrites can also aid neuron classification. Dendrites with spines are classified as spiny, those without spines are classified as aspinous. Stellate cells can be spiny or aspinous, while pyramidal cells are always spiny. Most common stellate cells are the inhibitory interneurons found within the upper half of the molecular layer in the cerebellum. Cerebellar stellate cells synapse onto the dendritic trees of Purkinje cells and send inhibitory signals. Stellate neurons are sometimes found in other locations in the central nervous system; cortical spiny stellate cells are found in layer IVC of the primary visual cortex. In the somatosensory barrel cortex of mice and rats, glutamatergic (excitatory) spiny stellate cells are organized in the barrels of layer 4. They receive excitatory synaptic fibres from the thalamus and process feed forward excitation to 2/3 layer of the primary visual cortex to pyramidal cells. Cortical spiny stellate cells have a 'regular' firing pattern. Stellate cells are chromophobes, that is cells that does not stain readily, and thus appears relatively pale under the microscope.

<span class="mw-page-title-main">Aura (symptom)</span> Symptom of epilepsy and migraine

An aura is a perceptual disturbance experienced by some with epilepsy or migraine. An epileptic aura is a seizure.

<span class="mw-page-title-main">SYNGAP1</span> Protein in Homo sapiens

Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a protein that in humans is encoded by the SYNGAP1 gene. SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans can cause intellectual disability, epilepsy, autism and sensory processing deficits.

<span class="mw-page-title-main">Environmental enrichment</span> Brain stimulation through physical and social surroundings

Environmental enrichment is the stimulation of the brain by its physical and social surroundings. Brains in richer, more stimulating environments have higher rates of synaptogenesis and more complex dendrite arbors, leading to increased brain activity. This effect takes place primarily during neurodevelopment, but also during adulthood to a lesser degree. With extra synapses there is also increased synapse activity, leading to an increased size and number of glial energy-support cells. Environmental enrichment also enhances capillary vasculation, providing the neurons and glial cells with extra energy. The neuropil expands, thickening the cortex. Research on rodent brains suggests that environmental enrichment may also lead to an increased rate of neurogenesis.

Activity-dependent plasticity is a form of functional and structural neuroplasticity that arises from the use of cognitive functions and personal experience; hence, it is the biological basis for learning and the formation of new memories. Activity-dependent plasticity is a form of neuroplasticity that arises from intrinsic or endogenous activity, as opposed to forms of neuroplasticity that arise from extrinsic or exogenous factors, such as electrical brain stimulation- or drug-induced neuroplasticity. The brain's ability to remodel itself forms the basis of the brain's capacity to retain memories, improve motor function, and enhance comprehension and speech amongst other things. It is this trait to retain and form memories that is associated with neural plasticity and therefore many of the functions individuals perform on a daily basis. This plasticity occurs as a result of changes in gene expression which are triggered by signaling cascades that are activated by various signaling molecules during increased neuronal activity.

<span class="mw-page-title-main">Nonsynaptic plasticity</span> Form of neuroplasticity

Nonsynaptic plasticity is a form of neuroplasticity that involves modification of ion channel function in the axon, dendrites, and cell body that results in specific changes in the integration of excitatory postsynaptic potentials and inhibitory postsynaptic potentials. Nonsynaptic plasticity is a modification of the intrinsic excitability of the neuron. It interacts with synaptic plasticity, but it is considered a separate entity from synaptic plasticity. Intrinsic modification of the electrical properties of neurons plays a role in many aspects of plasticity from homeostatic plasticity to learning and memory itself. Nonsynaptic plasticity affects synaptic integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the cellular level. These individual neuronal alterations can result in changes in higher brain function, especially learning and memory. However, as an emerging field in neuroscience, much of the knowledge about nonsynaptic plasticity is uncertain and still requires further investigation to better define its role in brain function and behavior.

Synaptic tagging, or the synaptic tagging hypothesis, was first proposed in 1997 by Julietta U. Frey and Richard G. Morris; it seeks to explain how neural signaling at a particular synapse creates a target for subsequent plasticity-related product (PRP) trafficking essential for sustained LTP and LTD. Although the molecular identity of the tags remains unknown, it has been established that they form as a result of high or low frequency stimulation, interact with incoming PRPs, and have a limited lifespan.

<span class="mw-page-title-main">Granule cell</span> Type of neuron with a very small cell body

The name granule cell has been used for a number of different types of neurons whose only common feature is that they all have very small cell bodies. Granule cells are found within the granular layer of the cerebellum, the dentate gyrus of the hippocampus, the superficial layer of the dorsal cochlear nucleus, the olfactory bulb, and the cerebral cortex.

Compartmental modelling of dendrites deals with multi-compartment modelling of the dendrites, to make the understanding of the electrical behavior of complex dendrites easier. Basically, compartmental modelling of dendrites is a very helpful tool to develop new biological neuron models. Dendrites are very important because they occupy the most membrane area in many of the neurons and give the neuron an ability to connect to thousands of other cells. Originally the dendrites were thought to have constant conductance and current but now it has been understood that they may have active Voltage-gated ion channels, which influences the firing properties of the neuron and also the response of neuron to synaptic inputs. Many mathematical models have been developed to understand the electric behavior of the dendrites. Dendrites tend to be very branchy and complex, so the compartmental approach to understand the electrical behavior of the dendrites makes it very useful.

Translational neuroscience is the field of study which applies neuroscience research to translate or develop into clinical applications and novel therapies for nervous system disorders. The field encompasses areas such as deep brain stimulation, brain machine interfaces, neurorehabilitation and the development of devices for the sensory nervous system such as the use of auditory implants, retinal implants, and electronic skins.

The GAERS or Genetic Absence Epilepsy Rat from Strasbourg is a recognized animal model of absence epilepsy, a typical childhood form of epilepsy characterized by recurrent loss of contact and concomitant pattern on the electroencephalogram called "spike-and-wave" discharges. It was first characterized in Strasbourg, France, in the 1980s and since then has been used by different international research groups to understand the mechanisms underlying absence seizures and their ontogeny, using different techniques.

<span class="mw-page-title-main">Yehezkel Ben-Ari</span> French neuroscientist specialized in the development of brain disorders

Yehezkel Ben-Ari is a neurobiologist specializing in brain development and the development of brain disorders. He has made seminal contributions to the understanding of brain activity in health and disease and notably autism, epilepsies and related infantile disorders.

References

  1. 1 2 3 "2019 Prize Winner - Eppendorf Corporate". corporate.eppendorf.com. Retrieved 2020-05-29.
  2. 1 2 3 4 5 6 "Lauren Orefice - Publications". neurotree.org. Retrieved 2020-05-29.
  3. 1 2 3 4 Orefice, Lauren L.; Heinrichs, Stephen C. (2008-02-01). "Paternal care paradoxically increases offspring seizure susceptibility in the El mouse model of epilepsy". Epilepsy & Behavior. 12 (2): 234–241. doi:10.1016/j.yebeh.2007.09.004. ISSN   1525-5050. PMID   17964859. S2CID   20540536.
  4. ↑ "Fresh Hires". B-SoCCS 2019. Retrieved 2020-05-29.
  5. 1 2 3 "A Light Touch". hms.harvard.edu. Retrieved 2020-05-29.
  6. 1 2 3 Orefice, Lauren L.; Waterhouse, Emily G.; Partridge, John G.; Lalchandani, Rupa R.; Vicini, Stefano; Xu, Baoji (2013-07-10). "Distinct Roles for Somatically and Dendritically Synthesized Brain-Derived Neurotrophic Factor in Morphogenesis of Dendritic Spines". Journal of Neuroscience. 33 (28): 11618–11632. doi:10.1523/JNEUROSCI.0012-13.2013. ISSN   0270-6474. PMC   3724547 . PMID   23843530.
  7. 1 2 3 4 Orefice, Lauren L.; Shih, Chien-Cheng; Xu, Haifei; Waterhouse, Emily G.; Xu, Baoji (2016-03-01). "Control of spine maturation and pruning through proBDNF synthesized and released in dendrites". Molecular and Cellular Neuroscience. 71: 66–79. doi:10.1016/j.mcn.2015.12.010. ISSN   1044-7431. PMC   4761458 . PMID   26705735.
  8. ↑ "Neurotree - Lauren Orefice". neurotree.org. Retrieved 2020-05-29.
  9. ↑ "2019 Prize Winner - Eppendorf Corporate". corporate.eppendorf.com. Retrieved 2020-05-29.
  10. 1 2 3 "Autism's social problems may stem from sense of touch". Spectrum | Autism Research News. 2016-06-09. Retrieved 2020-05-29.
  11. 1 2 3 4 "Research". Orefice Lab. Retrieved 2020-05-29.
  12. 1 2 3 4 5 6 Orefice, Lauren L.; Zimmerman, Amanda L.; Chirila, Anda M.; Sleboda, Steven J.; Head, Joshua P.; Ginty, David D. (2016-07-14). "Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs". Cell. 166 (2): 299–313. doi:10.1016/j.cell.2016.05.033. ISSN   0092-8674. PMC   5567792 . PMID   27293187.
  13. 1 2 3 Orefice, Lauren L.; Mosko, Jacqueline R.; Morency, Danielle T.; Wells, Michael F.; Tasnim, Aniqa; Mozeika, Shawn M.; Ye, Mengchen; Chirila, Anda M.; Emanuel, Alan J.; Rankin, Genelle; Fame, Ryann M. (2019-08-08). "Targeting Peripheral Somatosensory Neurons to Improve Tactile-Related Phenotypes in ASD Models". Cell. 178 (4): 867–886.e24. doi:10.1016/j.cell.2019.07.024. ISSN   0092-8674. PMC   6704376 . PMID   31398341.
  14. ↑ Orefice, Lauren L. (2019). "Outside-in: Rethinking the etiology of autism spectrum disorders". Science. 366 (6461): 45–46. doi:10.1126/science.aaz3880 . Retrieved May 28, 2020.
  15. ↑ "Pew Biomedical Scholars". pew.org. Retrieved 2020-09-03.
  16. ↑ "Searle Scholars Program names 15 scientists as Searle Scholars for 2020". Searle Scholars Program. Retrieved 2020-05-29.
  17. ↑ SelectScience. "American scientist wins 2019 Eppendorf & Science Prize | SelectScience". www.selectscience.net. Retrieved 2020-05-29.
  18. ↑ "Smith Family Awards Program for Excellence in Biomedical Research 2019 Award Recipients" (PDF). Retrieved May 28, 2020.
  19. ↑ "The Esther A. & and Joseph Klingenstein Fund, Inc". www.klingfund.org. Retrieved 2020-05-29.
  20. ↑ "Regeneron Announces the 2018 Winners of the Regeneron Prize for Creative Innovation". Regeneron Pharmaceuticals Inc. Retrieved 2020-05-29.
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