Translational and Clinical Neuroscience

Research Description

The goal of my basic science research is to understand the mechanisms by which genetic ion channel variants identified in patients with early-onset epilepsy translate to altered channel biophysics when isolated in an expression system, to abnormal intrinsic neuronal excitability when studied in patient-derived neurons (made from induced pluripotent stem cell lines), and to circuit-level disruption resulting in epileptogenesis in transgenic animal models. This three-pronged approach shares a common pathophysiologic protein, and is intended to identify new therapeutic targets by complementary ion channel, neuronal, and synaptic modulation.

For more information please view the faculty profile of Tracy Gertler, MD, PhD.

Publications

View Dr. Gertler's publications on PubMed.

Contact

Contact Tracy Gertler, MD, PhD, via email.

Research Description

Hao Li, PhD completed his PhD in neuroscience with Thomas Jhou, PhD, at the Medical University of South Carolina, studying circuit mechanisms underlying punishment processing. In 2019, Li started his postdoctoral training with Kay Tye, PhD, at the Salk Institute, focusing on how neurotensin guides valence assignment in the amygdala during associative learning. Dr. Li's lab utilizes cutting-edge circuit and systems approaches to study how neural circuits and neuropeptides regulate emotion. Li's specific interests include 1) understanding how neuropeptides exert long-lasting neuromodulatory effects on circuits and regulate emotional states, 2) identifying risk factors contributing to addiction vulnerability and resilience, 3) investigating neural mechanisms underlying observational social aggression, and 4) exploring how brain-body connection can regulate emotion. The Li Lab's ultimate aim is to advance the quest for better treatments for mental health disorders.

Publications

Contact

320 East Superior Street
Suite 4-490
Chicago, IL 60611

For inquiries about this research, please contact haoli@northwestern.edu or visit The Li Lab website.

Research Description

Meltzer is the director of the Translational Neuropharmacology Program at Feinberg. His research interests include research interests include: basic and clinical psychopharmacology, pharmacogenomics, and prevention of suicide.

Publications

See Dr. Meltzer's publications on PubMed.

Contact

For contact information, please see Dr. Meltzer's faculty profile.

Research Description

In an effort to identify more efficacious therapeutics, Reesha Patel, PhD seeks to investigate the mechanistic impact of previously understudied contributing factors including social stress and neuroimmune signaling on discrete neuronal circuits, and how they give rise to aberrant behavioral phenotypes associated with stress-related mental health disorders.

Publications

See Dr. Patel's publications on PubMed.

Contact

320 East Superior Street
Suite 4-691
Chicago, IL 60611

For inquiries about this research, please contact reesha.patel@northwestern.edu or visit The Patel Lab for more information.

Research Description

The research program led by Sachin Patel, MD, PhD, focuses on the role of endocannabinoids in stress-induced neuroadaptation. Psychosocial stress is a key trigger for the development and exacerbation of a variety of psychiatric disorders. By understanding the molecular, structural and physiological adaptations in endocannabinoid signaling that occur in response to stress, they hope to uncover novel targets for drug development. In addition, the lab uses a variety of techniques to understand the role of endocannabinoids in the brain's response to stress, with the hope that these investigations will provide insight into the pathophysiology of stress-related neuropsychiatric disorders.

Current Projects

Endocannabinoid modulation of stress responsivity

The lab aims to understand the role of the endocannabinoid 2-arachidonoylglycerol in the regulation of behavioral, endocrine and synaptic adaptations induced by stress. They use a variety of approaches including electrophysiology, optogenetics, calcium imaging, behavioral pharmacology and genetics combined with mouse behavior to address these questions. Elucidating how 2-AG signaling adapts to stress could reveal novel endocannabinoid-based approaches to the treatment of stress-relates psychiatric disorders.

Experience-dependent plasticity in amygdala circuits

The lab is interested in how amygdala circuits and distinct cell types are functionally organized to orchestrate behavioral responses to stress and how these circuits adapt in response to stress exposure. They utilize optogenetics, chemogenetics, electrophysiology and models of Pavlovian fear learning and extinction to address these questions.

For details and images, visit the lab site.

Publications

See Dr. Patel's publications on PubMed.

Contact

320 East Superior Street
Suite 400
Chicago, IL 60611

For inquiries about this research, please contact alexander.white@northwestern.edu.

Research Description

Research in my laboratory centers on the molecular and cellular mechanisms that control the formation and modification of dendritic spines in the mammalian brain. These mechanisms underlie the normal development and plasticity of the brain, and contribute to higher brain functions, including cognitive, social, and communication behavior. However, when these mechanisms go awry, they lead to mental and neurological disorders. Our analysis integrates multiple organizational levels, from molecular, cellular, circuit, and rodent models, to human subjects. We employ both a “translational” strategy, utilizing basic mechanistic data we generate to understand disease pathogenesis, and a “reverse-translational” strategy, in which genetic, neuropathological, and imaging studies in human subjects help guide the discovery of novel mechanistic insight. The ultimate goal of these studies is to develop therapeutic approaches to prevent or reverse neuropsychiatric disorders, by targeting mechanisms that control dendritic spines and synapses.

• Mechanistic studies on the molecular mechanisms of dendritic spine plasticity: This line of research aims to identify and elucidate functions of novel molecular regulators of synaptic circuit modification during the lifespan. We investigate the formation, remodeling, and elimination of spiny synapses in neurons using both in vitro and in vivo models. We are particularly interested in signaling, adhesion, and scaffolding molecules that control cell-to-cell communication and mediate intracellular signaling by neurotransmitter receptors. My laboratory continues to investigate small GTPase pathways and the roles of guanine-nucleotide exchange factors, such as kalirin and Epac2, and their downstream targets Rac, PAK, Rap and Ras. In addition, we have made important contributions to understanding how synaptic activity controls synapse size and strength through a pathway involving NMDA receptors, CaMKII, kalirin, Rac1 and actin, how rapid synaptic plasticity in the brain is regulated by locally synthesized estrogen, how adhesion molecules including N-cadherin control synapse size and strength, and how dopamine and neuroligin control synapse stability though Epac2 and Rap1.
• Translational and reverse-translational studies on the molecular substrates of dendritic spine pathology: Investigations of genetic, neuropathological, and neuromorphological alterations in human subjects with psychiatric disorders have started to reveal the pathogenic mechanisms behind these illnesses, and are also guiding the discovery of unexpected basic mechanisms of brain development and function. Through studies performed in the lab and through collaborations, we investigate molecular and cellular alterations occurring in patients with schizophrenia, bipolar disorder, autism, and Alzheimer’s disease. We then use model systems, such as neuronal cultures or mice, to elucidate the functions and pathogenic mechanisms of key molecules. We are currently investigating the basic synaptic functions of several leading mental disorder risk genes, to understand how they contribute to normal brain function and to synapse pathology. Conversely, many molecules we have been studying in the lab have more recently been implicated in the pathogenesis of mental disorders through independent neuropathological or genetic studies. We have shown that molecules that control basic synapse structural plasticity, such as kalirin and Epac2, functionally interact with leading mental disorder risk molecules, such as neuregulin1, ErbB4, DISC1, 5HT2A receptors, dopamine receptors, neuroligin, and Shank3. We have generated mutant mice in which kalirin or Epac2 are ablated, and have shown that these molecules control behaviors relevant for mental disorders, such as sociability, working memory, sensory motor gating, and vocalizations. These animal models can thus help to understand the synaptic substrates of specific aspects of mental disorders. To investigate the abnormal regulation of these molecular pathways in schizophrenia, autism, Alzheimer’s disease, and the impact of these molecular abnormalities on disease phenotypes in human subjects, we are collaborating with neuropathologists, brain imaging experts, and geneticists who investigate human subjects.

Therapeutic reversal of neuropsychiatric disease by targeting synaptic connectivity. By harnessing the knowledge from our basic and reverse-translational studies, my goal is to develop novel therapeutic approaches to prevent, delay, or reverse the course of mental and neurodegenerative disorders. Because abnormal synaptic connections play central roles in the pathogenesis of schizophrenia, autism, and Alzheimer’s disease, pharmacological targeting of key molecules implicated in synaptic plasticity and pathology can rescue disease associated abnormalities, and thereby influence the outcome of the disease. We are currently developing transgenic animal models to validate synaptic signaling molecules as therapeutic targets in mental disorders. We are also developing cellular assays which we will use in high-throughput screens for small-molecule regulators of synapse remodeling. Our goal is to identify small-molecule regulators of synapse remodeling which can be taken into clinical trials as therapeutics aimed at reversing synaptic deficits, and thus cognitive dysfunction, in mental disorders.

In our studies, we employ a multidisciplinary approach, using an array of methods that include advanced cellular and in vivo microscopy, biochemistry, electrophysiology, manipulations of gene expression in vivo, mouse behavioral analysis, circuit mapping, and human genetics and neuropathology.

For lab information and more, see Dr. Penzes' faculty profile.

Publications

See Dr. Penzes' publications on PubMed.

Contact

Contact Dr. Penzes at 312-503-5379.

Research Description

We perceive the world by actively sampling it, e.g., by eye movements and head turns. Our memory of past experiences is thus often coupled with our actions in the environment. How does our brain internally integrate our actions into perception and memory of the perceived world? Our lab will address this question by focusing on dream perception during sleep. How does our brain internally generate dreams where we can act and perceive so vividly? Answering this question will provide clues to the nature of our internal generative model of the world, which is also crucial for our awake perception. To this end, our lab focuses on the superior colliculus as a central hub orchestrating perception and learning during wakefulness and sleep. The superior colliculus is not only critical for sensory-motor integration, but also interacts tightly with thalamocortical networks important for vision, action, navigation, and memory formation. Our lab combines cutting-edge technologies in freely behaving and sleeping mice, such as chronic large-scale electrophysiological recordings, decoding neuronal representation, opto- and chemogenetics, eye movement monitoring, behavioral analysis, and computational techniques.

For lab information and more, see Dr. Senzai's faculty profile and lab website.

Publications

See Dr. Senzai's publications on PubMed.

Contact

Contact Dr. Senzai.