I am a Research Health Scientist at VA Boston Healthcare System (VA BHS) and an Associate Professor of Psychiatry at Harvard Medical School. I am an affiliated faculty member and associate preceptor of the Division of Sleep Medicine. My laboratory at the West Roxbury campus of VA BHS studies the sleep-wake cycle and brain electrical rhythms in mice. I am the PI of a VA Merit award and an NIMH R01 grant. I am also an investigator on 4 other NIH/VA grants. My scholarship includes 46 original peer-reviewed articles & 9 peer-reviewed review articles, many of which are highly cited (average 74 citations per publication; 20 articles with >50 citations). I have given local, national and international presentations of my work. I served as the chair of the Scientific Review Committee of the Sleep Research Society for two years and I am currently Associate Editor at Frontiers in Neuroscience, Sleep and circadian rhythms section. I have reviewed grant proposals for NIH, DoD and other scientific organizations around the world. I currently act as a mentor for three postdoctoral fellows and three Assistant Professors at VA BHS. Many of my previous mentees have gone on to senior faculty positions in the US, Europe and Asia. I am course director/neuroscience expert for the South Shore Residency Program for HMS psychiatry residents at VA BHS, a member of the program evaluation committee and the local HMS promotions committee.
SOCIETY MEMBERSHIPS: Sleep Research Society (SRS)
CURRENT TRAINEES: Fumi Katsuki, Felipe Schiffino (co-mentored with Robert Strecker), David Uygun co-mentored with Radhika Basheer).
RESEARCH HIGHLIGHTS: In 1999, the sleep disorder narcolepsy was shown to be caused by degeneration of orexin neurons. While a postdoctoral researcher in Germany I reported the excitatory effects of the orexins on wake-promoting aminergic neurons (4 articles with >150 citations). My scientific findings have been translated into practice in several important ways. The loss of the orexin/hypocretin effects I demonstrated is thought to explain several symptoms of narcolepsy, such as excessive daytime sleepiness and sleep-associated hallucinations. As such, a new drug, Belsomra, which antagonizes brain orexin/hypocretin receptors was recently approved by the FDA as a novel treatment for insomnia. In addition, the orexin excitation of ventral tegmental area dopamine neurons, which we demonstrated for the first time (Korotkova et al., 2003, > 300 citations, Brown senior author) has been implicated in reinstatement of drug addiction.
Synthesis of knowledge and formation of theory concerning cellular mechanisms which control sleep-wake behavior. I have authored 9 comprehensive review articles and 4 book chapters which summarize our current knowledge of the cellular mechanisms controlling sleep-wakefulness and EEG. This includes a review of the physiology of the brain histamine system, the most recently discovered of the brain aminergic systems (Brown et al., 2001; >700 citations). Based on this review I proposed the brain histamine system is a “danger response system” which acts to increase wakefulness and alertness and suppress unnecessary systems (e.g. feeding) in the short-term in response to threats. More recently, I was the first author and major writer of an unusually comprehensive (100 page, 1479 references) review of sleep-wake mechanisms published in Physiological reviews, the most highly cited physiology journal. This review (Brown et al., 2012) was selected as a highly cited article in field of biology and biochemistry by essential science indicators (Thomson Reuters) and has ~500 citations.
Identification of the cellular properties and functional role of GABAergic neurons regulating arousal and REM sleep (reviewed in Brown and McKenna, 2015). Pharmacological agents which enhance GABAergic neurotransmission represent a major class of anxiolytic, hypnotic and anesthetic drugs. However, surprisingly little is known about the location, subtypes and properties of GABAergic neurons controlling the sleep-wake cycle due to technical difficulties in identification. My group validated a novel genetic tool expressing green fluorescent protein in GABAergic neurons (GAD67-GFP knock-in mice) to investigate the properties of GABAergic neurons involved in sleep-wake control and cortical rhythms. We showed that GFP selectively labels GABAergic neurons (Brown et al., 2008; McNally et al., 2011; McKenna et al., 2013) and confirmed that sleep-wake behavior (Chen et al., 2010) and cortical rhythms are normal (McNally et al., 2011). Using these mice, I performed the first electrophysiological recordings from identified GABAergic neurons in the brainstem involved in control of REM sleep (Brown et al., 2008) and basal forebrain (BF) GABAergic neurons projecting to the neocortex (McKenna et al., 2013). My mentee and I found that these BF GABA neurons are excited by neighboring cholinergic neurons (Yang et al., 2014) and together with other investigators in the department we found that these neurons regulate cortical gamma oscillations (Kim et al., 2015). These findings represent a paradigm shift away from a cholinergic-centric view of BF control of arousal towards a model whereby cholinergic neurons work together with neighboring GABAergic neurons to ‘wake up the cortex’. The BF is severely affected in Alzheimer’s disease and other types of dementia. Thus, our results may have important implications for the treatment of the cognitive impairments associated with these conditions.
Control of neocortical gamma band oscillations (GBO; 30-80 Hz). Cortical GBO are involved in cognitive functions such as attention and working memory and are abnormal in several neuropsychiatric disorders, in particular, schizophrenia. Designing treatments to correct GBO abnormalities requires better methods to elicit them in reduced preparations and a better understanding of their state-dependent control. My postdoc and I developed a novel method to elicit GBO in neocortical slices in vitro (McNally et al., 2011). We found using this method that the psychomimetic and rapidly acting anti-depressant, ketamine, causes GBO abnormalities which mimic those observed in schizophrenia (McNally et al., 2011, 2013). Recently our group found that GBO are regulated by inputs from a particular subcortical system, basal forebrain parvalbumin neurons (Kim et al., PNAS 2015). These results identify two potential avenues to develop novel therapeutic agents to correct GBO abnormalities: a) study of effects on cortical circuitry using our novel in vitro method and; b) modulation of the activity level of basal forebrain parvalbumin neurons. In recent work, we are manipulating this system to study the understand the symptoms of schizophrenia (McNally et al., under review) and improve the pathophysiology in Alzheimer’s disease model mice (Schiffino et al., unpublished). Furthermore, our preliminary work suggests a role of the basal forebrain system in control of attention and rescuing the effects of sleep deprivation (Felipe Schiffino F32 application selected for funding).
Control of sleep spindles by the thalamic reticular nucleus. Abnormalities in sleep spindles, a 10-15 Hz, waxing and waning oscillation observed in light non-REM sleep have been linked to deficits in memory consolidation in schizophrenia. Our major findings/advances are as follows: (i) We published two complementary methods to investigate sleep spindles and their dysfunction in neurophysiological disorders (Prerau et a., 2017; Uygun et al., 2019); (ii) Using a novel paradigm of optogenetic stimulation of thalamic reticular nucleus (TRN) parvalbumin (PV) neurons we can elicit ‘naturalistic’ sleep spindles (Thankachan, Katsuki et al., 2019) without altering behavioral state, a major methodological advance which facilitates our ongoing work to test the role of spindles in sleep-dependent memory consolidation; (iii) The type of T-type calcium channels most highly expressed in TRN, Cav3.3, is a Sz risk gene. We found that pharmacological blockade of T-type calcium channels in TRN inhibited sleep spindles without affecting NREM sleep time or cortical delta band activity (Thankachan et al., 2019); (iv) Optogenetic stimulation studies revealed that the Basal forebrain GABA/PV input to TRN regulates sleep spindles and wakefulness (Thankachan, Katsuki et al., 2019). (v) Manipulations of TRN activity also modulate other electrophysiological features of schizophrenia, cortical gamma (30-80 Hz) and delta oscillations (1-4 Hz) during wakefulness (Thankachan, Katsuki et al., 2019). These results suggest that manipulations of the activity of TRN PV neurons or their major input arising from basal forebrain PV neurons may be beneficial in correcting electrophysiological abnormalities observed in schizophrenia and promote sleep-dependent memory consolidation.
TEACHING. I serve as a course director and basic neuroscience expert in teaching 3 separate courses to psychiatry residents at the Brockton campus of VA BHS. I have developed innovative curricula for these courses. The teaching focus is on having residents learn how to talk about neuroscience and apply it in their clinical work. For example, in my course ‘Eat. Sleep, Exercise’, after teaching physiology and neuroscience, I have students role-play how to teach their patients about the science underlying patients’ challenges with eating, sleep and exercising. In “From Synapses to Systems” I work one-on-one with residents to help them prepare to teach their peers about various neuroscience topics. In the ‘Neuroscience Seminar” for third year residents I cover a wide range of cutting-edge neuroscience topics and test the residents on the knowledge needed to pass the Psychiatry Resident In Training Exam (PRITE). These courses are well-received by residents as they appreciate the translation from bench to bedside.
SUMMARY. My research aims to reveal the brain circuits and cellular mechanisms which wake us up and put us to sleep. I apply this knowledge to animal models of neuropsychiatric disease in order to design rational treatments and disseminate this knowledge through the writing of comprehensive review articles and book chapters, training junior researchers and teaching medical residents.