Neurosciences

Ram Shukla

Rammohan Shukla, PH.D.

Ram Shukla
Assistant Professor
Office: 182 Block Health Science Building
Tel: 419-383-4506
Email:  Rammohan.Shukla@UToledo.Edu

Overarching goal:Most psychiatric disorders lack an identifiable origin and, unlike other medical disciplines where biomarkers are well established, psychiatric disorders are classified using descriptive criteria, typically manifesting as behavioral dysfunction, resulting in phenotypic complexity. For instance, using a combination of 18 DSM-IV listed items, more than 3000 different forms of attention-deficit/hyperactivity disorder (ADHD) can be defined. The dysregulation underlying this phenotypic complexity extends to various biological levels, including cells that form brain and cortical microcircuits, as well as the numerous genes and functional pathways. Understanding this phenotypic complexity at various biological levels is instrumental in explaining fundamental neurobiological processes and developing therapeutics. My present research focuses on better understanding the molecular and microcircuitry-based mechanisms governing the similarities and dissimilarities between different psychiatric disorders with a therapeutic endpoint.

Approaches and strategies:For a mechanistic understanding of complex psychiatric disorders, it is necessary to understand their heterogeneity. I envision a research program that leads to the convergence of high throughput omics technologies, data-science, computational biophysical modelling of neuronal microcircuitry, animal behavior, and drug discovery.  This program comprises the following key strategic directions.

First, examine age-related changes to better understand baseline homeostatic changes and compare them to psychiatric illnesses, as deviations from the baseline. For this, I use high throughput omic-based data either generated by myself or obtained from publicly available resources. My analysis workflow entails inferring cell-specific causality through Bayesian-network (BN) inference and then building druggable hypotheses focusing on them by utilizing publicly available drug-related molecular signature databases.

Second, Information is processed in cortical brain regions by canonical cell microcircuits formed by recurrent connections between neurons. Comprehending fundamental and altered microcircuitry mechanisms and associated nonlinear interaction between neurons, which contribute to the brain complexity, is key to the understanding of psychiatric disorders. To do this, I am developing a workflow to integrate single cell transcriptomics derived ontologies with biophysical modeling of neurons. Due to its extremely penetrant microcircuitry-dependent output, I am using data acquired from epilepsy rodent models to refine my workflow,

Third, design in-vitro and in-vivo experiments to test the druggable hypothesis and microcircuitry-based mechanisms.  

 

My recent (selected) publications highlighting my research program:

1. Smail MA, Chandrasena SS, Zhang X, Reddy V, Herman JP, Sherif M and Shukla R. Differential vulnerability of Anterior cingulate cortex cell-types to disease and drugs. (2021) bioRxiv.  doi: https://doi.org/10.1101/2021.10.26.465972 

2. Alnafisah RS, Reigle J, O’Donovan Sinead, Funk AJ, Meller J Mccullumsmith R and Shukla R. Pharmacological impacts on schizophrenia functional analysis: a postmortem proteome study. (2021) Neuropsychopharmacology

3. Reedy V, Sherif M, and Shukla R. Integrating single-cell transcriptomics and microcircuit computer modelling (2021) Current Opinion in Pharmacology

4. Smail MA, Wu X, Henkel ND, Eby HM, Herman JP, Mccullumsmith RE, and Shukla R. Similarities and dissimilarities between psychiatric cluster disorders.(2021) Molecular Psychiatry

5. Wu X, Shukla R*, Alganem K, Depasquale E, Reigle J, Meller J, Mccullumsmith R. Transcriptional profile of pyramidal neurons in chronic schizophrenia reveals lamina-specific dysfunction of neuronal immunity. (2021). Molecular Psychiatry *Equal contribution

 6. Tomoda T, Sumitomo A, Shukla R, Hirota-Tsuyada Y, Miyachi H, Oh H, French L, and Sibille E. BDNF controls neuropsychiatric manifestation via autophagic regulation of p62 and GABAA receptor trafficking. (2021) Neuropsychopharmacology.

7. Henkel ND, Smail MA, Wu X, Enright HA, Fisher N, Eby HM, Mccullumsmith R and Shukla R. Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy. (2021) Scientific Report

8. Shukla R*, Newton D, Sumitomo A, Zare H, Mccullumsmith R, Lewis D, Tomoda T, and Sibille E. Molecular Characterization of Depression Trait and State.(2021) Molecular Psychiatry. *Communicating author

9. Newton DF, Oh H, Shukla R, Misquitta K, Fee C, Banasr M and Sibille E. Chronic stress induces coordinated cortical microcircuit cell-type transcriptomic changes consistent with altered information processing. (2021) Biological Psychiatry

10. Shukla R*, Henkel N, Alganem K, Hamoud A, Reigle J, Alnafisah RS, et al. Signature based approches for Informed Drug Repurposing: Targeting CNS Disorders.(2020) Neuropsychopharmacology. *Communicating author 

11. Shukla R, Oh H, Sibille E. Molecular and cellular evidence for age by disease interactions: updatesand path forward. (2019) American Journal of Geriatric Psychiatry

12. Shukla R, Prevot TD, French L, Isserlin R, Rocco BR, Banasr M,and Sibille E. The relative contributions ofcell-dependent cortical microcircuit aging to cognition and anxiety. (2019) Biological Psychiatry.

 

Last Updated: 6/27/22