- Email: [email protected]
Jacqueline Crawley
Neuron
Q&A Jacqueline Crawley Dr. Jacqueline Crawley aims to understand the genetic causes of autism spectrum disorder and discover effective medical therapeutics for the core diagnostic symptoms of autism using rodent models. In an interview with Neuron, she shares her career milestones, aspirations and guiding principles inspiring her ongoing work. Jacqueline N. Crawley, PhD, is the Robert E. Chason Endowed Chair in Translational Research at the MIND Institute and Distinguished Professor in the Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, in Sacramento. Dr. Crawley received her BA in biology from the University of Pennsylvania and PhD in zoology from the University of Maryland College Park. She conducted postdoctoral research in neuropsychopharmacology at Yale University School of Medicine. As a principal investigator at the National Institute of Mental Health Intramural Research Program in Bethesda, Maryland, since 1983, she served as Chief of the Laboratory of Behavioral Neuroscience until moving to the UC Davis MIND Institute in 2012. Her behavioral neuroscience laboratory has employed mouse and rat models of anxiety, depression, schizophrenia, Alzheimer’s disease, and neurodevelopmental disorders to understand biological causes and to discover medical treatments. Recent work in her laboratory on genetic mouse models of autism identified GABA-A and GABA-B receptor agonists and mGluR5 and AMPA receptor modulators, which improved aspects of social interaction and reduced repetitive behaviors in mouse models. She has published more than 270 papers and 100 reviews; served on numerous editorial boards, scientific advisory, and grant review committees; received honors, including the IBNS Myers Lifetime Achievement Award, IBANGS Distinguished Scientist Award, NIMH Director’s Award, UC Davis Dean’s Award; and chaired the Summer Neuropeptide Conference and AAAS Neuroscience Section. Her sole authored book, What’s Wrong With My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice, is widely used by the biomedical research community.
2 Neuron 104, October 9, 2019
these large databases to discover the gene mutations and variants that mediate psychiatric, neurodevelopmental, neurodegenerative, and neurological syndromes. Risk genes that confer susceptibility to a disease are likely to interact with background genes that determine severity. Compensatory genes that confer protection from a disease could translate into powerful therapeutic targets.
Jacqueline N. Crawley MIND Institute and University of California Davis School of Medicine
What future direction in neuroscience are you most excited about? How would you like to see neuroscience evolve? The future of large-scale human genomic databases is astonishing. As wholegenome sequencing becomes increasingly affordable and as major initiatives such as NIH’s All of Us, Simons Foundation’s SPARK, Autism Speaks’ MSSNG, and analogous sequencing projects in Europe and Asia come to fruition, it will become possible to dissect the specific roles of multiple genes and their modifiers as determinants of health and disease. Proteomics and epigenetic screens offer complementary human datasets. I would like to see the neuroscience community recruit a generation of computational geneticists who will comprehensively mine
In your opinion, what are the most pressing questions for the field? CRISPR gene editing of human embryos will happen in our lifetime, for better or worse. For better, diseases can be eliminated in utero or with in vitro fertilization in cases of known family history. For worse, designer babies will become the norm, as in Aldous Huxley’s Brave New World. Currently, practical obstacles are being surmounted. The pressing question for the near-term future is which applications are ethical and which are not. Once decisions are made, how will regulations be enforced worldwide? Insights into CRISPR-Cas9 and Cas12 strategies, genetic biohacking, and regulatory options appear in the July 5, 2019, issue of Science, 365(6448), and many other journal articles. What are the questions that inspire your lab? Genetic determinants of autism were first indicated in 1977 in twin studies by Susan Folstein and Sir Michael Rutter. In 2007, Thomas Bourgeron and coworkers at the Institut Pasteur in Paris discovered the first gene, SHANK3, in which de novo mutations were strongly associated with cases of autism spectrum disorder. Discoveries of single gene mutations, copy number variants, and epigenetic and environmental factors contributing risk for autism have come thick and fast over the past 20 years.
Neuron
Q&A Many of the implicated genes code for synaptic proteins. Many are elements of downstream signaling pathways. Molecular genetics laboratories began generating lines of mice with syntenic mutations, which offer translational mouse models of autism with high construct validity. We were inspired by the intriguing question of how to model the unique behavioral symptoms of autism in mice. With the help of many wonderful clinical colleagues, we climbed the steep learning curve to understand the specific types of social deficits, repetitive behaviors, and sensory abnormalities that are common in people with autism. We were the first to develop a constellation of relevant mouse behavioral assays with high face validity and to phenotype the consequences of each mutation using mouse behaviors relevant to diagnostic and associated symptoms of autism, along with appropriate control measures. Our lab members have had opportunities to characterize autism-relevant behaviors in dozens of mouse models of autism, in collaboration with other labs which characterize the electrophysiological, neuroanatomical, neurochemical, gene expression, and synaptic morphology phenotypes in the same mutant lines. The goal of this strategy is to work out which genes might be responsible for which symptoms of autism and through which mechanisms. The strongest mouse models have become useful translational tools for testing hypotheses about pharmacological targets for therapeutic interventions at the level of synapse functions. The current inspiring question is whether the hundreds of genetic anomalies discovered in people with autism might act through convergent mechanisms, synergizing downstream to produce the core symptoms of autism. What is your guiding philosophy for running your lab? Your personal philosophy? Each lab member is equally deserving of opportunities to contribute to the biomedical research enterprise. From our postdoctoral fellows, graduate students, postbaccalaureates, technicians, undergraduate volunteers, Howard Hughes high school students, to collabo-
rators and visiting scientists, to the animal caretakers, housecleaning crew, security guards, shop engineers, IT experts, librarians, financial and personnel administrators, to the top leaders at universities and institutes, everybody’s contribution is essential to research success. Everyone matters. What motivated you to become a scientist? Scientific questions are absolutely the most interesting ideas to think about. Head and shoulders above the intellectual environment of any other career path. What career paths did you consider other than a scientist? In graduate school, when contemplating the concept of flunking out of science, my backup plan was check-out girl at the local Giant supermarket. What has been the highlight of your career? One day in 1997, an editor at John Wiley & Sons, Ann Boyle, walked into my office at NIMH and persuaded me to write a book. She cited a pressing need for a behavioral expert to explain tests of mouse behaviors to molecular geneticists who had generated mutant lines of mice that targeted genes expressed in the brain. At the time, our lab was one of the few in the world that had tested behaviors in a large number of mouse and rat models of neuropsychiatric diseases and had expertise in a wide range of rodent behavioral assays. What luck that I let Ann appeal to my vanity. What’s Wrong With My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice became a compendium for a generation of biomedical researchers. A highlight of my career has been the honor and thrill, when giving seminars at universities, to see my book on the shelf above student desks. Do you have a favorite anecdote from doing science that you’d like to share, perhaps a key discovery moment? A team of us led by Steve Paul in the NIMH intramural program in Bethesda, Maryland, discovered that the benzodiazepine Ro15-4513 antagonized ethanol intoxication in rats (Suzdak et al., Science 1986,
JPET 1988). What a thought! You could take a pill, drink all night, drive home safely, and feel fine the next morning! Irish Public Radio called for an interview on St. Patrick’s Day. Sadly, pharma was uninterested in developing Ro15-4513 for this indication. If only one person was insensitive to the drug and drove into a tree, the company would be sued into bankruptcy. Plus, liver damage persisted. Who were your key early influences? It has been my great good fortune to be influenced by truly inspiring mentors. Graduate advisors Wolfgang Schleidt, who discovered mouse pup ultrasonic vocalizations as a prote´ge´ of Nobel-Prizewinning ethologist Konrad Lorenz, and catecholamine neurochemist Joseph Contrera, in the University of Maryland Department of Zoology, enabled my doit-yourself neuroscience dissertation research, back when the word ‘‘neuroscience’’ was just coined. Psychology Professor Bill Hodos took us to the first Society for Neuroscience meeting at the Shoreham Hotel in Washington, DC, in 1971. Postdoctoral advisors and faculty in the Yale neuropsychopharmacology training program, including Jim Maas, Bob Roth, George Aghajanian, Susan Haddox, and Steve Bunney, introduced me to catecholamine pharmacology, locus coeruleus stimulation, gas chromatography, and mass spectrometry. At NIMH, I was lucky to work with the brilliant Steve Paul when he discovered endogenous ligands of the benzodiazepine receptor. These included beta carbolines, purines, and neurosteroids. My lab tested these candidate ligands for anxiety-related behaviors using a mouse conflict test that I invented, light4dark transitions, with the help of NIMH engineers Bruce Smith and George Dold. Tomas Ho¨kfelt at the Karolinska Institute in Stockholm made the iconoclastic discovery that neuropeptides coexist within the same neurons as classical neurotransmitters. Tomas inspired our behavioral analyses of the modulatory role of cholecystokinin coexisting with dopamine in the mesolimbic pathway, of galanin coexisting with acetylcholine in the basal forebrain, and of neuropeptide
Neuron 104, October 9, 2019 3
Neuron
Q&A Y and galanin coexisting with norepinephrine in the locus coeruleus. In addition to being an incredibly productive neuroscientist, Tomas is an impeccable gentleman. Everything I know about proper professional manners I learned from him. Cathy Lord, Joe Piven, Geri Dawson, Uta Frith, Sue Swedo, Audrey Thurm, and many phenomenal MIND Institute investigators, including Sally Rogers, Marjorie Solomon, and Sally Ozonoff, taught me about the diagnostic and associated symptoms of autism, which we then attempted to model in mice. Their generosity in sharing observational opportunities allowed us to develop the three-chambered social approach test, in collaboration with Sheryl Moy, Jessica Nadler, and Joe Piven at the University of North Carolina. A continually intriguing question is whether social cognition is a subset of general cognition and whether social communication is a subset of general communication. The great fun of scientific research has been endlessly enhanced by my interactions with smart, giving mentors. What’s your favorite experiment? Some people with neurodevelopmental disorders harbor mutations in GABA receptors, loss of GABA interneurons, and/ or impaired downstream signaling mechanisms, which reduce inhibitory neurotransmission. Over the past 5 years, work in our lab and others identified GABA-A and GABA-B receptor agonists that reduced repetitive behaviors and improved aspects of sociability in various mouse models of autism spectrum disorders (Silverman et al., 2015; Stoppel et al., 2018; Rhine et al., 2019). The translational goal of these preclinical experiments is to discover drug treatments that could benefit a stratified subset of people with autism. Our most recent paper, translating the genius of Gary Lynch, revealed that spaced training trials improved learning in genetic mouse models of Down and Angelman syndromes, as compared to massed training trials (Lauterborn et al., 2019). Distributed learning is a well-established principle of human learning. Cramming for an exam is less effective than several learning sessions spaced over time. This principle has not been
4 Neuron 104, October 9, 2019
systematically tested in people with neurodevelopmental disorders that include cognitive impairment. Our findings in two disparate mouse models, Ts65Dn and Ube3a, replicated across two labs, suggest a more efficacious teaching method for children and adults with intellectual disabilities. To tackle your favorite research question, is there a tool that either needs to be developed or is currently available that could be implemented in a novel way? Ultrasonic vocalizations are emitted by mice during social interactions. Our former postdoctoral fellow Maria Luisa Scattoni was the first to categorize the characteristic shapes of ultrasonic calls. She compared patterns of call categories across different social settings and in different lines of mice (Scattoni et al., 2008, 2011). However, a fundamental question remains to be answered: do vocalizations have a communication function in adult mice? If yes, then mouse ultrasonic vocalizations with unusual organizations of call categories could be used as a key assay to model the types of social communication abnormalities seen in people with autism. Playback experiments to investigate the communication function of juvenile and adult mouse calls have been technically difficult to design. Tools are needed to (1) deliver simulated vocalizations, e.g., a miniature speaker headset that can be attached near the mouse’s ears, and (2) record responses in the target mouse, e.g., a miniature microphone necklace attached near the mouse’s mouth. What do you think are the biggest problems/challenges science as a whole is facing today? The constant struggle for grant funding has turned science into a business. Everyone has to hustle to sell their product. It seems that results must be presented with undue fanfare and hyperbole when giving talks, writing grant applications, having conversations with program officers at funding agencies, schmoozing with colleagues, and getting a paper published in a high-profile journal. Principal investigators communicate this unfortunate tendency to their graduate students
and postdocs. Somehow, we need to return to the excitement of rigorous scientific research, the crystallizing joy of discovery. It’s a calling, not a job. What do you think are the biggest possibilities/challenges for the education of future scientists? Early and mid-career scientists are expected to take on too many responsibilities during their most productive research years. Serving on university committees, grant review study sections, and teaching large undergraduate classes takes faculty away from the lab. Love of research dies from burnout. I would suggest harnessing the wisdom, experience, and free time of older faculty for these important contributions to the academic enterprise. Superlative education of future scientists from grade school through graduate school could come from volunteer teachers who had been successful researchers, perhaps during their first years after retirement. Which aspect of science—your field or in general—would you wish the general public knew more about? The general public would benefit immensely from simply understanding the basic scientific method, i.e., how to discover facts and solve problems. Ask the right question, design the best experiment, run the testing correctly, interpret the results accurately. Listen to what the data are telling you about cause and effect. What advice do you find yourself giving to your students and postdocs? Accept the big intellectual challenges. Pursue the most interesting, important questions in which your unique talents can make a meaningful contribution. This is what we have tried to do with our lab’s expertise in rodent behavioral neuroscience. Replicate your findings. The first time a student or postdoc discovers something interesting, that’s a poster at the Society for Neuroscience meeting. When they replicate their results in a second, independent set of experiments, they’ve got a publication. When the finding replicates a third time, then I believe it.
Neuron
Q&A Most importantly, hang in there. Scientists have to be able to function on a long reinforcement schedule. Most experiments don’t work. The one that does— you’ve just discovered a new true fact. Maybe a fundamental biological principle! How do you find inspiration? Reading journal articles, listening to seminar lectures, talking with colleagues when we go out to lunch and hang out over beers at conferences. I am incredibly grateful to the many smart, dedicated investigators in the NIH intramural program and the UC Davis MIND Institute, whose insightful research inspired a multitude of productive collaborations.
What do you do when you’re not in the lab? Yes, you can have a life outside the lab. Our son and daughter-in-law, who are both postdoctoral researchers, had a baby girl this year. Helping them out with her is now my favorite extracurricular activity. If you are similarly a young postdoc or graduate student thinking about when to start your family, go for it. There is no perfect time for a scientist to have a baby. The solution is to marshal an army of assistants. Enlist all of the family help you can recruit. Spend your money on highquality daycare, babysitters, and housekeepers to do the cleaning and laundry. Do your shopping online, have dinner
delivered. Don’t worry about going broke—you’ll earn more later. Freeing yourself from mundane tasks will allow you to devote your time and energy to your children, partner, and career. The key is to avoid exhaustion. You don’t want to miss out on the precious, irretrievable early years when your kids need you the most. If you could ask an omniscient higher being one scientific question, what would it be and why? Is there advanced life elsewhere in the universe? What does it look like? Where do humans fall on the cosmic intelligence spectrum? https://doi.org/10.1016/j.neuron.2019.09.021
Neuron 104, October 9, 2019 5
Q&A Jacqueline Crawley Dr. Jacqueline Crawley aims to understand the genetic causes of autism spectrum disorder and discover effective medical therapeutics for the core diagnostic symptoms of autism using rodent models. In an interview with Neuron, she shares her career milestones, aspirations and guiding principles inspiring her ongoing work. Jacqueline N. Crawley, PhD, is the Robert E. Chason Endowed Chair in Translational Research at the MIND Institute and Distinguished Professor in the Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, in Sacramento. Dr. Crawley received her BA in biology from the University of Pennsylvania and PhD in zoology from the University of Maryland College Park. She conducted postdoctoral research in neuropsychopharmacology at Yale University School of Medicine. As a principal investigator at the National Institute of Mental Health Intramural Research Program in Bethesda, Maryland, since 1983, she served as Chief of the Laboratory of Behavioral Neuroscience until moving to the UC Davis MIND Institute in 2012. Her behavioral neuroscience laboratory has employed mouse and rat models of anxiety, depression, schizophrenia, Alzheimer’s disease, and neurodevelopmental disorders to understand biological causes and to discover medical treatments. Recent work in her laboratory on genetic mouse models of autism identified GABA-A and GABA-B receptor agonists and mGluR5 and AMPA receptor modulators, which improved aspects of social interaction and reduced repetitive behaviors in mouse models. She has published more than 270 papers and 100 reviews; served on numerous editorial boards, scientific advisory, and grant review committees; received honors, including the IBNS Myers Lifetime Achievement Award, IBANGS Distinguished Scientist Award, NIMH Director’s Award, UC Davis Dean’s Award; and chaired the Summer Neuropeptide Conference and AAAS Neuroscience Section. Her sole authored book, What’s Wrong With My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice, is widely used by the biomedical research community.
2 Neuron 104, October 9, 2019
these large databases to discover the gene mutations and variants that mediate psychiatric, neurodevelopmental, neurodegenerative, and neurological syndromes. Risk genes that confer susceptibility to a disease are likely to interact with background genes that determine severity. Compensatory genes that confer protection from a disease could translate into powerful therapeutic targets.
Jacqueline N. Crawley MIND Institute and University of California Davis School of Medicine
What future direction in neuroscience are you most excited about? How would you like to see neuroscience evolve? The future of large-scale human genomic databases is astonishing. As wholegenome sequencing becomes increasingly affordable and as major initiatives such as NIH’s All of Us, Simons Foundation’s SPARK, Autism Speaks’ MSSNG, and analogous sequencing projects in Europe and Asia come to fruition, it will become possible to dissect the specific roles of multiple genes and their modifiers as determinants of health and disease. Proteomics and epigenetic screens offer complementary human datasets. I would like to see the neuroscience community recruit a generation of computational geneticists who will comprehensively mine
In your opinion, what are the most pressing questions for the field? CRISPR gene editing of human embryos will happen in our lifetime, for better or worse. For better, diseases can be eliminated in utero or with in vitro fertilization in cases of known family history. For worse, designer babies will become the norm, as in Aldous Huxley’s Brave New World. Currently, practical obstacles are being surmounted. The pressing question for the near-term future is which applications are ethical and which are not. Once decisions are made, how will regulations be enforced worldwide? Insights into CRISPR-Cas9 and Cas12 strategies, genetic biohacking, and regulatory options appear in the July 5, 2019, issue of Science, 365(6448), and many other journal articles. What are the questions that inspire your lab? Genetic determinants of autism were first indicated in 1977 in twin studies by Susan Folstein and Sir Michael Rutter. In 2007, Thomas Bourgeron and coworkers at the Institut Pasteur in Paris discovered the first gene, SHANK3, in which de novo mutations were strongly associated with cases of autism spectrum disorder. Discoveries of single gene mutations, copy number variants, and epigenetic and environmental factors contributing risk for autism have come thick and fast over the past 20 years.
Neuron
Q&A Many of the implicated genes code for synaptic proteins. Many are elements of downstream signaling pathways. Molecular genetics laboratories began generating lines of mice with syntenic mutations, which offer translational mouse models of autism with high construct validity. We were inspired by the intriguing question of how to model the unique behavioral symptoms of autism in mice. With the help of many wonderful clinical colleagues, we climbed the steep learning curve to understand the specific types of social deficits, repetitive behaviors, and sensory abnormalities that are common in people with autism. We were the first to develop a constellation of relevant mouse behavioral assays with high face validity and to phenotype the consequences of each mutation using mouse behaviors relevant to diagnostic and associated symptoms of autism, along with appropriate control measures. Our lab members have had opportunities to characterize autism-relevant behaviors in dozens of mouse models of autism, in collaboration with other labs which characterize the electrophysiological, neuroanatomical, neurochemical, gene expression, and synaptic morphology phenotypes in the same mutant lines. The goal of this strategy is to work out which genes might be responsible for which symptoms of autism and through which mechanisms. The strongest mouse models have become useful translational tools for testing hypotheses about pharmacological targets for therapeutic interventions at the level of synapse functions. The current inspiring question is whether the hundreds of genetic anomalies discovered in people with autism might act through convergent mechanisms, synergizing downstream to produce the core symptoms of autism. What is your guiding philosophy for running your lab? Your personal philosophy? Each lab member is equally deserving of opportunities to contribute to the biomedical research enterprise. From our postdoctoral fellows, graduate students, postbaccalaureates, technicians, undergraduate volunteers, Howard Hughes high school students, to collabo-
rators and visiting scientists, to the animal caretakers, housecleaning crew, security guards, shop engineers, IT experts, librarians, financial and personnel administrators, to the top leaders at universities and institutes, everybody’s contribution is essential to research success. Everyone matters. What motivated you to become a scientist? Scientific questions are absolutely the most interesting ideas to think about. Head and shoulders above the intellectual environment of any other career path. What career paths did you consider other than a scientist? In graduate school, when contemplating the concept of flunking out of science, my backup plan was check-out girl at the local Giant supermarket. What has been the highlight of your career? One day in 1997, an editor at John Wiley & Sons, Ann Boyle, walked into my office at NIMH and persuaded me to write a book. She cited a pressing need for a behavioral expert to explain tests of mouse behaviors to molecular geneticists who had generated mutant lines of mice that targeted genes expressed in the brain. At the time, our lab was one of the few in the world that had tested behaviors in a large number of mouse and rat models of neuropsychiatric diseases and had expertise in a wide range of rodent behavioral assays. What luck that I let Ann appeal to my vanity. What’s Wrong With My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice became a compendium for a generation of biomedical researchers. A highlight of my career has been the honor and thrill, when giving seminars at universities, to see my book on the shelf above student desks. Do you have a favorite anecdote from doing science that you’d like to share, perhaps a key discovery moment? A team of us led by Steve Paul in the NIMH intramural program in Bethesda, Maryland, discovered that the benzodiazepine Ro15-4513 antagonized ethanol intoxication in rats (Suzdak et al., Science 1986,
JPET 1988). What a thought! You could take a pill, drink all night, drive home safely, and feel fine the next morning! Irish Public Radio called for an interview on St. Patrick’s Day. Sadly, pharma was uninterested in developing Ro15-4513 for this indication. If only one person was insensitive to the drug and drove into a tree, the company would be sued into bankruptcy. Plus, liver damage persisted. Who were your key early influences? It has been my great good fortune to be influenced by truly inspiring mentors. Graduate advisors Wolfgang Schleidt, who discovered mouse pup ultrasonic vocalizations as a prote´ge´ of Nobel-Prizewinning ethologist Konrad Lorenz, and catecholamine neurochemist Joseph Contrera, in the University of Maryland Department of Zoology, enabled my doit-yourself neuroscience dissertation research, back when the word ‘‘neuroscience’’ was just coined. Psychology Professor Bill Hodos took us to the first Society for Neuroscience meeting at the Shoreham Hotel in Washington, DC, in 1971. Postdoctoral advisors and faculty in the Yale neuropsychopharmacology training program, including Jim Maas, Bob Roth, George Aghajanian, Susan Haddox, and Steve Bunney, introduced me to catecholamine pharmacology, locus coeruleus stimulation, gas chromatography, and mass spectrometry. At NIMH, I was lucky to work with the brilliant Steve Paul when he discovered endogenous ligands of the benzodiazepine receptor. These included beta carbolines, purines, and neurosteroids. My lab tested these candidate ligands for anxiety-related behaviors using a mouse conflict test that I invented, light4dark transitions, with the help of NIMH engineers Bruce Smith and George Dold. Tomas Ho¨kfelt at the Karolinska Institute in Stockholm made the iconoclastic discovery that neuropeptides coexist within the same neurons as classical neurotransmitters. Tomas inspired our behavioral analyses of the modulatory role of cholecystokinin coexisting with dopamine in the mesolimbic pathway, of galanin coexisting with acetylcholine in the basal forebrain, and of neuropeptide
Neuron 104, October 9, 2019 3
Neuron
Q&A Y and galanin coexisting with norepinephrine in the locus coeruleus. In addition to being an incredibly productive neuroscientist, Tomas is an impeccable gentleman. Everything I know about proper professional manners I learned from him. Cathy Lord, Joe Piven, Geri Dawson, Uta Frith, Sue Swedo, Audrey Thurm, and many phenomenal MIND Institute investigators, including Sally Rogers, Marjorie Solomon, and Sally Ozonoff, taught me about the diagnostic and associated symptoms of autism, which we then attempted to model in mice. Their generosity in sharing observational opportunities allowed us to develop the three-chambered social approach test, in collaboration with Sheryl Moy, Jessica Nadler, and Joe Piven at the University of North Carolina. A continually intriguing question is whether social cognition is a subset of general cognition and whether social communication is a subset of general communication. The great fun of scientific research has been endlessly enhanced by my interactions with smart, giving mentors. What’s your favorite experiment? Some people with neurodevelopmental disorders harbor mutations in GABA receptors, loss of GABA interneurons, and/ or impaired downstream signaling mechanisms, which reduce inhibitory neurotransmission. Over the past 5 years, work in our lab and others identified GABA-A and GABA-B receptor agonists that reduced repetitive behaviors and improved aspects of sociability in various mouse models of autism spectrum disorders (Silverman et al., 2015; Stoppel et al., 2018; Rhine et al., 2019). The translational goal of these preclinical experiments is to discover drug treatments that could benefit a stratified subset of people with autism. Our most recent paper, translating the genius of Gary Lynch, revealed that spaced training trials improved learning in genetic mouse models of Down and Angelman syndromes, as compared to massed training trials (Lauterborn et al., 2019). Distributed learning is a well-established principle of human learning. Cramming for an exam is less effective than several learning sessions spaced over time. This principle has not been
4 Neuron 104, October 9, 2019
systematically tested in people with neurodevelopmental disorders that include cognitive impairment. Our findings in two disparate mouse models, Ts65Dn and Ube3a, replicated across two labs, suggest a more efficacious teaching method for children and adults with intellectual disabilities. To tackle your favorite research question, is there a tool that either needs to be developed or is currently available that could be implemented in a novel way? Ultrasonic vocalizations are emitted by mice during social interactions. Our former postdoctoral fellow Maria Luisa Scattoni was the first to categorize the characteristic shapes of ultrasonic calls. She compared patterns of call categories across different social settings and in different lines of mice (Scattoni et al., 2008, 2011). However, a fundamental question remains to be answered: do vocalizations have a communication function in adult mice? If yes, then mouse ultrasonic vocalizations with unusual organizations of call categories could be used as a key assay to model the types of social communication abnormalities seen in people with autism. Playback experiments to investigate the communication function of juvenile and adult mouse calls have been technically difficult to design. Tools are needed to (1) deliver simulated vocalizations, e.g., a miniature speaker headset that can be attached near the mouse’s ears, and (2) record responses in the target mouse, e.g., a miniature microphone necklace attached near the mouse’s mouth. What do you think are the biggest problems/challenges science as a whole is facing today? The constant struggle for grant funding has turned science into a business. Everyone has to hustle to sell their product. It seems that results must be presented with undue fanfare and hyperbole when giving talks, writing grant applications, having conversations with program officers at funding agencies, schmoozing with colleagues, and getting a paper published in a high-profile journal. Principal investigators communicate this unfortunate tendency to their graduate students
and postdocs. Somehow, we need to return to the excitement of rigorous scientific research, the crystallizing joy of discovery. It’s a calling, not a job. What do you think are the biggest possibilities/challenges for the education of future scientists? Early and mid-career scientists are expected to take on too many responsibilities during their most productive research years. Serving on university committees, grant review study sections, and teaching large undergraduate classes takes faculty away from the lab. Love of research dies from burnout. I would suggest harnessing the wisdom, experience, and free time of older faculty for these important contributions to the academic enterprise. Superlative education of future scientists from grade school through graduate school could come from volunteer teachers who had been successful researchers, perhaps during their first years after retirement. Which aspect of science—your field or in general—would you wish the general public knew more about? The general public would benefit immensely from simply understanding the basic scientific method, i.e., how to discover facts and solve problems. Ask the right question, design the best experiment, run the testing correctly, interpret the results accurately. Listen to what the data are telling you about cause and effect. What advice do you find yourself giving to your students and postdocs? Accept the big intellectual challenges. Pursue the most interesting, important questions in which your unique talents can make a meaningful contribution. This is what we have tried to do with our lab’s expertise in rodent behavioral neuroscience. Replicate your findings. The first time a student or postdoc discovers something interesting, that’s a poster at the Society for Neuroscience meeting. When they replicate their results in a second, independent set of experiments, they’ve got a publication. When the finding replicates a third time, then I believe it.
Neuron
Q&A Most importantly, hang in there. Scientists have to be able to function on a long reinforcement schedule. Most experiments don’t work. The one that does— you’ve just discovered a new true fact. Maybe a fundamental biological principle! How do you find inspiration? Reading journal articles, listening to seminar lectures, talking with colleagues when we go out to lunch and hang out over beers at conferences. I am incredibly grateful to the many smart, dedicated investigators in the NIH intramural program and the UC Davis MIND Institute, whose insightful research inspired a multitude of productive collaborations.
What do you do when you’re not in the lab? Yes, you can have a life outside the lab. Our son and daughter-in-law, who are both postdoctoral researchers, had a baby girl this year. Helping them out with her is now my favorite extracurricular activity. If you are similarly a young postdoc or graduate student thinking about when to start your family, go for it. There is no perfect time for a scientist to have a baby. The solution is to marshal an army of assistants. Enlist all of the family help you can recruit. Spend your money on highquality daycare, babysitters, and housekeepers to do the cleaning and laundry. Do your shopping online, have dinner
delivered. Don’t worry about going broke—you’ll earn more later. Freeing yourself from mundane tasks will allow you to devote your time and energy to your children, partner, and career. The key is to avoid exhaustion. You don’t want to miss out on the precious, irretrievable early years when your kids need you the most. If you could ask an omniscient higher being one scientific question, what would it be and why? Is there advanced life elsewhere in the universe? What does it look like? Where do humans fall on the cosmic intelligence spectrum? https://doi.org/10.1016/j.neuron.2019.09.021
Neuron 104, October 9, 2019 5