Department of Physiology and Biophysics
University of Colorado School of Medicine
RC1 North Tower, P18-7121
Mail Stop 8307
Aurora, CO 80045
We are a lab that works on cholinergic signaling in the mammalian brain. Cholinergic systems, via the actions of released acetylocholine, are thought to play an essential role in behaviors involving attention, learning and memory. Impairment of cholinergic signaling is implicated in many neurodegenerative diseases likes Alzheimer's and Parkinson's; and in psychiatric disorders like schizophrenia. However, we know very little about mechanisms underlying signaling by this important neurotransmitter. Our lab strives to remedy this deficit in our knowledge.
Sagittal section of brain from a ChATtau GFP mouse showing the major cholinergic pathways from the medial septum (MS) and Ventral limb of the diagonal band of Broca (VDB) to the hippocampus (Hipp; arrows). The brightly fluorescent pathway is the cholinergic innervation from the medial habenula (MHB) to the Interpeduncular nucleus.
We look at how endogenous cholinergic signaling modulates synaptic transmission and plasticity in the hippocampus and the olfactory bulb. We also use defined circuits of principal neurons and inhibitory interneurons in order to ask how cholinergic receptors regulate the input-output relationships of a circuit and how this modulation affects behavior.
A. A cartoon of the olfactory circuit showing location of nicotinic receptors (purple rectangles) and muscarinic receptors (red rectangles). Activation of these receptors in the glomerular microcircuit trigger excitation-dependent inhibition from GABAergic interneurons resulting in the setting up of a high-pass filter where weak inputs are filtered out while strong ones are transmitted. B. A model for nicotinic modulation of circuit output. In the absence of nicotinic modulation both strong and weak inputs are transmitted (depicted by the arrows). In the presence of receptor activation (Filter ON) weak inputs are filtered out. For details see D’Souza and Vijayaraghavan (2014).
Another area of research examines the differences between the actions of nicotine (as happens in smokers) and the endogenous transmitter that addresses the question of addiction and how exposure to nicotine might alter endogenous signaling in the brain.
A&B Responses of a hippocampal CA3 pyramidal neuron to application of 0.5 µM nicotine, concentration seen in the serum of smokers. A. Application of nicotine (red area) causes a large increase in the frequency of mEPSCs in this cell. B. The same cell under current clamp. Application of nicotine causes burst firing of the pyramidal cell. C & D Endogenous nicotinic signaling. Acetylcholine release was triggered optically in mice that express channelrhodopsin in cholinergic neurons. When a 10 ms stimulus was applied (at the arrows), brief bursts of high frequency sEPSCs were elicited (black trace) which was attenuated by a nicotinic antagonist (red trace). D. Same cell under current clamp- stimulation of ACh release resulted in depolarization and firing of the pyramidal cell.
A recent project in the lab hopes to link, mechanistically, olfactory insults and neurodegeneration: It has been documented that loss of smell in one of the earliest symptoms seen in people suffering from Parkinson's disease and Alzheimer's disease, preceding all canonical symptoms by as much as a few years. We ask if olfactory loss is mechanistically related to neuronal death in the brain. Our initial finding that injecting 6-hydroxydopamine (6-OHDA) in the olfactory bulb results in a large loss of dopaminergic neurons in the substantia nigra suggests the existence of such a link, possibly via direct inputs from the substantia nigra to the olfactory bulb.
A. A dopamine neurotoxin, 6-Hydroxydopamine (6-OHDA) was injected unilaterally into the olfactory bulb of a mouse, the injection site is marked by co-injection of a dye (orange fluorescent area). The other side was injected with saline. B. Tyrosine hydroxylase staining in the midbrain showing dopaminergic neurons of the substantia nigra. Notice the large loss in the number of dopaminergic neurons in the substantia nigra (to your right) ipsilateral to the site of 6-OHDA injection.
Very well...Thank you! We use a number of transgenic and gene knockout mouse models to answer our questions. Our experiments involve combinations of slice electrophysiology (and, soon to come, in vivo recordings), calcium imaging, optogenetics, immunohistochemistry, CLARITY, confocal and light-sheet microscopy as well as many other techniques we deem necessary to answer our questions.
People with imagination who are curious and excited about science in general.
Spindle MS, Parsa PV, Bowles SG, D’Souza RD, Vijayaraghavan S. (2018). A dominant role for the beta 4 nicotinic receptor subunit in nicotinic modulation of glomerular microcircuits in the mouse olfactory bulb. J. Neurophys. 120, 2036-2048.
Parsa, PV, D’Souza RD and Vijayaraghavaan, S. (2015) Signaling between periglomerular cells reveals a bimodal role for GABA in modulating glomerular microcircuitry in the olfactory bulb . Proc. Natl. Acad. Sci. 30, 9478-9483.
D’Souza, RD and Vijayaraghavan, S. (2014). Paying attention to smell. Front. Syn. Neurosci. 6, 21
D’Souza, RD, Parsa, PV and Vijayaraghavan, S. (2013). Nicotinic receptors modulate olfactory bulb external tufted cells via an excitation-dependent inhibitory mechanism. J.Neurophysiol. 110, 1544-1553.
D’Souza, R.D. and Vijayaraghavan,S. (2012). α3β4 Nicotinic Receptors Filter Mitral Cell Responses to Olfactory Nerve Inputs. J. Neurosci. 32, 3261-3266.
Salcedo, E., Tran, T., Ly, X., Lopez, R., Barbica, C.,Restrepo, D., and Vijayaraghavan, S. (2011) Activity-Dependent Changes in Cholinergic Innervation of the Mouse Olfactory Bulb. PLOS1. e25441.
Grybko, M.J., Hahm, E-t, Perrine, W., Parnes, J.A., Chick, W.S., Sharma, G., Finger, T.E., and Vijayaraghavan, S. (2011). A Transgenic Mouse Model Reveals Fast Nicotinic Transmission in Hippocampal Pyramidal Neurons. Eur. J. Neurosci. 33, 1786-1798.
Grybko, M., Sharma, G., and Vijayaraghavan, S. (2010). Functional Distribution of the a7 Subtype of Nicotinic Receptors in CA3 Region of the Hippocampus. J.Mol. Neurosci. 40, 114-120.
Vijayaraghavan, S. (2009). Glial-neuronal interactions- implications for plasticity and drug addiction. AAPS J. 11, 123-132.
Sharma, S., Grybko, M., and Vijayaraghavan, S. (2008). Action Potential-Independent and Nicotinic Receptor Mediated Concerted Release of Multiple Quanta at Hippocampal CA3-Mossy Fiber Synapses. J. Neurosci. 28, 2563-2575.
Ghatpande, A.S., Sivaraaman, K., and Vijayaraghavan, S. (2006). Store Calcium Mediates Cholinergic effects on mIPSCs in the Rat Main Olfactory Bulb. J. Neurophysiol. 95, 1345-1355.
Sharma, G. and Vijayaraghavan, S. (2003). Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing. Neuron 38, 929-939.