Dr. Smitha Karunakaran
Research Interest: Circuit mechanisms underlying dementia including Alzheimer’s Disease
Profile: Dr. Karunakaran received her degrees from Kasturba Medical College (MSc. Medical Biochemistry, 2000) and National Brain Research Centre (PhD. 2009). Her PhD was focused on the molecular mechanisms underlying the selective neuronal vulnerability in Parkinson’s Disease. She completed her postdoctoral training at the Friedrich Miescher Institute (FMI) in Basel studying the neural circuit mechanisms involved in long term memory consolidation. She joined CBR in 2017, where her laboratory now employs multidisciplinary approaches to study how early perturbation in fundamental neuronal circuits contribute to the early cognitive symptoms in Alzheimer’s disease.
Neural circuits and behaviour
The primary goal of our laboratory is to understand the neural circuit-based mechanisms underlying early behavioural manifestations of Alzheimer’s disease (AD).
AD is an irreversible, progressive neurodegenerative disorder that slowly impairs memory and higher cognitive functions. Longitudinal studies in humans have revealed that the pathogenic processes of AD start decades before the clinical onset of the disease. One of the first brain regions to be affected early on in AD is the hippocampus, a region critically involved in learning and memory processes. Learning requires precise neuronal communication across widely distributed brain networks centred around the hippocampus. Our laboratory investigates how hippocampal projecting neurons/systems such as the locus coeruleus (LC) -noradrenergic system transform hippocampal network dynamics and modulate behaviour during early stages of AD.
We use transgenic mice as a model system carrying familial AD mutations which mimic the pathological and behavioural hallmarks of the disease. The model allows us to ask specific questions about the underlying biology of AD progression. Applying this approach, we initially investigate the nature and dynamics of early behavioural deficits using quantitative behavioural assays relevant to the symptoms of AD. We further combine these quantitative behavioural assays with viral tracings and ma¬¬-nipulation of genetically defined cell types such as LC neurons using pharmacogenetics to causally assess the contribution of individual circuit elements to a particular aspect of behavioural output. The combination of these approaches enables us to delineate how neural circuit alterations influence behaviour during early AD.
Hippocampal circuitry in early Alzheimer’s Disease: Using different hippocampal dependent and independent behaviour paradigms we primarily seek to understand the hippocampal circuit deficits, and how they contribute to early behavioural impairments in AD mouse model.
Role of Locus Coeruleus in maintaining cognitive function in normal and pathological ageing, such as dementia: In this project we aim to characterise the specific subset of LC neurons and their output targets affected during early AD, and their role in early behavioural impairments using AD mouse model.
Present lab members
Mr. Abhijith Shankaran
M. Sc (Molecular Biology and Human Genetics)
School of Life Sciences, Manipal Academy of Higher Education, Manipal
Currently working on: Role of Locus Coeruleus in maintaining cognitive function in normal and pathological ageing, such as dementia
Former lab members
Ruchika Mahesh Agarwal,
MSc Medical Biotechnology, MS University, Baroda, Gujarat.
Shanice Jessica Hermon,
Integrated MSc student, NISER, Bhubaneswar.
Integrated MSc Life Sciences, Central University of Jharkhand, Jharkhand.
- Karunakaran S*. Early beta adrenoceptor dependent time window for fear memory persistence in APPswe/PS1dE9 mice.Sci Rep. 2021, 11:870. PMID: 334415
- Karunakaran S*.Unraveling Early Signs of Navigational Impairment in APPswe/PS1dE9 Mice Using Morris Water Maze. Front Neurosci. 2020,14:568200. PMID: 33384577
- Barodia SK, Prabhakaran K, Karunakaran S, Mishra V, Tapias V. Editorial: Mitochondria and Endoplasmic Reticulum Dysfunction in Parkinson’s Disease. Front Neurosci. 2019 Nov 8 :1171. PMID: 31780882
- Kommaddi RP, Tomar DS, Karunakaran S, Bapat D, Nanguneri S, Ray A, Schneider BL, Nair D, Ravindranath V. Glutaredoxin1 Diminishes Amyloid Beta-Mediated Oxidation of F-Actin and Reverses Cognitive Deficits in an Alzheimer’s Disease Mouse Model. Antioxid Redox Signal. 2019 Dec 20:1321-1338. PMID: 31617375
- Kommaddi RP, Das D, Karunakaran S, Nanguneri S, Bapat D, Ray A, Shaw E, Bennett DA, Nair D, Ravindranath V. ABeta mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer’s disease. J Neurosci. 2017 Dec 15: 2127-17. PMID:29246925
- Karunakaran S, Chowdhury A, Donato F, Quairiaux C, Michel CM, Caroni P. PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation. Nat Neurosci. 2016 Mar;19(3):454-64. PMID:26807952.
- Ray A, Sehgal N, Karunakaran S, Rangarajan G, Ravindranath V. Dopaminergic toxin MPTP activates ASK1-p38 MAPK death signaling pathway through TNF-dependent thioredoxin oxidation in Parkinsonism mouse model. Free Radic Biol Med. 2015 Oct; 87: 312-25. PMID: 26164633.
- Saeed U, Karunakaran S, Meka DP, Koumar RC, Ramakrishnan S, Joshi SD, Prakash N, Ravindranath V. Redox activated MAP kinase death signalling cascade initiated by ASK1 is not activated in female mice following MPTP – novel mechanism of neuroprotection. Neurotox Res. 2009 Aug; 16(2): 116-26. PMID: 1952628
- Karunakaran S and Ravindranath V. Activation of p38 MAP kinase in the substantia nigra leads to nuclear translocation of NF-kB in MPTP treated mice: Implication in Parkinson’s disease. J Neurochem. 2009 May 11; 109(6): 1791-1799. PMID: 19457134
- Karunakaran S, Saeed U, Mishra M, Valli RK, Joshi SD, Meka DP, Seth P, Ravindranath V. Selective activation of p38 MAP kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in MPTP treated mice. J Neurosci. 2008 Nov 19; 28(47): 12500-12509. PMID: 19020042
- Karunakaran S, Saeed U, Ramakrishnan S, Koumar RC, Ravindranath V.Constitutive expression and functional characterization of mitochondrial glutaredoxin (Grx2) in mouse and human brain. Brain Res. 2007 Dec 14; 1185:8 – 17. PMID: 17961515
- Karunakaran S, Diwakar L, Saeed U, Agarwal V, Ramakrishnan S, Iyengar S, Ravindranath V. Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson’s disease: protection by alpha-lipoic acid. FASEB J. 2007 Jul; 21(9): 2226 – 36. PMID: 17369508
PhD positions available
Project assistant position available
Centre for Brain Research
Indian Institute of Science (IISc)
Malleswaram 18th Cross
Telephone: Office +91 80 2293 3588