Zayd M. Khaliq, Ph.D.

Position

Joint Faculty (with NINDS), Behavioral Neuroscience Research Branch
Senior Investigator, Cellular Neurophysiology Section (NINDS)

Contact

Building 35
35 Convent Drive
Room 3C-1002
Bethesda, MD 20892-3700

Phone: 301-451-7221

Email: zayd.khaliq@nih.gov

Education

Ph.D. - Neuroscience - Northwestern University - Illinois

B.A.- Physics - Dartmouth College - New Hampshire

Background

Dr. Khaliq received his B.A. in Physics from Dartmouth College and his Ph.D. in Neuroscience from Northwestern University in 2006. During his graduate work with Indira Raman, he studied the initiation and propagation of action potentials in cerebellar Purkinje neurons. During his postdoctoral fellowship with Bruce Bean at Harvard Medical School, he studied the ionic mechanisms of firing in dopamine-releasing neurons located in the ventral tegmental area (VTA) and substantia nigra. He joined NINDS as an Investigator in 2011. His laboratory is focused on the cellular and synaptic mechanisms of neuronal firing within the midbrain dopamine system.

Research Interests

Zayd M. Khaliq, Ph.D. is a joint faculty member at the National Institute on Drug Abuse (NIDA) and the National Institute of Neurological Disorders and Stroke (NINDS), where he is chief of the Cellular Neurophysiology Section. His research focuses on dopamine-releasing neurons located in the midbrain, which play an essential role in movement and reward-based behaviors. Dysfunction of these neurons has been linked to a variety of brain disorders including addiction, schizophrenia, depression and Parkinson’s disease. The goal of our research is to understand 1) how voltage-gated ion channels contribute to excitability and action potential firing of dopamine neurons and other neurons that participate in reward circuits, 2) how synaptic inputs interact with intrinsic membrane conductances to produce spiking patterns that are relevant to reward-based learning, 3) and how neuromodulatory inputs influence excitability of these neurons. We address these questions using patch-clamp techniques to record the activity of neurons in brain slices. We combine this approach with imaging, immunohistochemistry and the use of transgenic mice to identify specific populations of neurons within the reward circuit.

Cellular Neurophysiology Section – NINDS

Selected Publications

2020

Evans, Rebekah C; Twedell, Emily L; Zhu, Manhua; Ascencio, Jefferson; Zhang, Renshu; Khaliq, Zayd M

Functional Dissection of Basal Ganglia Inhibitory Inputs onto Substantia Nigra Dopaminergic Neurons Journal Article

In: Cell Rep, vol. 32, no. 11, pp. 108156, 2020, ISSN: 2211-1247.

Abstract | Links

Kramer, Paul F; Twedell, Emily L; Shin, Jung Hoon; Zhang, Renshu; Khaliq, Zayd M

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release Journal Article

In: Elife, vol. 9, 2020, ISSN: 2050-084X.

Abstract | Links

2018

Philippart, Fabian; Khaliq, Zayd M

G protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN Journal Article

In: Elife, vol. 7, 2018, ISSN: 2050-084X.

Abstract | Links

2017

Evans, Rebekah C; Zhu, Manhua; Khaliq, Zayd M

Dopamine Inhibition Differentially Controls Excitability of Substantia Nigra Dopamine Neuron Subpopulations through T-Type Calcium Channels Journal Article

In: J Neurosci, vol. 37, no. 13, pp. 3704–3720, 2017, ISSN: 1529-2401.

Abstract | Links

@article{pmid28264982,

title = {Dopamine Inhibition Differentially Controls Excitability of Substantia Nigra Dopamine Neuron Subpopulations through T-Type Calcium Channels},

author = {Rebekah C Evans and Manhua Zhu and Zayd M Khaliq},

url = {https://pubmed.ncbi.nlm.nih.gov/28264982/},

doi = {10.1523/JNEUROSCI.0117-17.2017},

issn = {1529-2401},

year  = {2017},

date = {2017-01-01},

urldate = {2017-01-01},

journal = {J Neurosci},

volume = {37},

number = {13},

pages = {3704--3720},

abstract = {While there is growing appreciation for diversity among ventral tegmental area dopamine neurons, much less is known regarding functional heterogeneity among the substantia nigra pars compacta (SNc) neurons. Here, we show that calbindin-positive dorsal tier and calbindin-negative ventral tier SNc dopaminergic neurons in mice comprise functionally distinct subpopulations distinguished by their dendritic calcium signaling, rebound excitation, and physiological responses to dopamine D2-receptor (D2) autoinhibition. While dopamine is known to inhibit action potential backpropagation, our experiments revealed an unexpected enhancement of excitatory responses and dendritic calcium signals in the presence of D2-receptor inhibition. Specifically, dopamine inhibition and direct hyperpolarization enabled the generation of low-threshold depolarizations that occurred in an all-or-none or graded manner, due to recruitment of T-type calcium channels. Interestingly, these effects occurred selectively in calbindin-negative dopaminergic neurons within the SNc. Thus, calbindin-positive and calbindin-negative SNc neurons differ substantially in their calcium channel composition and efficacy of excitatory inputs in the presence of dopamine inhibition. Substantia nigra dopaminergic neurons can be divided into two populations: the calbindin-negative ventral tier, which is vulnerable to neurodegeneration in Parkinson's disease, and the calbindin-positive dorsal tier, which is relatively resilient. Although tonic firing is similar in these subpopulations, we find that their responses to dopamine-mediated inhibition are strikingly different. During inhibition, calbindin-negative neurons exhibit increased sensitivity to excitatory inputs, which can then trigger large dendritic calcium transients due to strong expression of T-type calcium channels. Therefore, SNc neurons differ substantially in their calcium channel composition, which may contribute to their differential vulnerability. Furthermore, T-currents increase excitation efficacy onto calbindin-negative cells during dopamine inhibition, suggesting that shared inputs are differentially processed in subpopulations resulting in distinct downstream dopamine signals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

While there is growing appreciation for diversity among ventral tegmental area dopamine neurons, much less is known regarding functional heterogeneity among the substantia nigra pars compacta (SNc) neurons. Here, we show that calbindin-positive dorsal tier and calbindin-negative ventral tier SNc dopaminergic neurons in mice comprise functionally distinct subpopulations distinguished by their dendritic calcium signaling, rebound excitation, and physiological responses to dopamine D2-receptor (D2) autoinhibition. While dopamine is known to inhibit action potential backpropagation, our experiments revealed an unexpected enhancement of excitatory responses and dendritic calcium signals in the presence of D2-receptor inhibition. Specifically, dopamine inhibition and direct hyperpolarization enabled the generation of low-threshold depolarizations that occurred in an all-or-none or graded manner, due to recruitment of T-type calcium channels. Interestingly, these effects occurred selectively in calbindin-negative dopaminergic neurons within the SNc. Thus, calbindin-positive and calbindin-negative SNc neurons differ substantially in their calcium channel composition and efficacy of excitatory inputs in the presence of dopamine inhibition. Substantia nigra dopaminergic neurons can be divided into two populations: the calbindin-negative ventral tier, which is vulnerable to neurodegeneration in Parkinson's disease, and the calbindin-positive dorsal tier, which is relatively resilient. Although tonic firing is similar in these subpopulations, we find that their responses to dopamine-mediated inhibition are strikingly different. During inhibition, calbindin-negative neurons exhibit increased sensitivity to excitatory inputs, which can then trigger large dendritic calcium transients due to strong expression of T-type calcium channels. Therefore, SNc neurons differ substantially in their calcium channel composition, which may contribute to their differential vulnerability. Furthermore, T-currents increase excitation efficacy onto calbindin-negative cells during dopamine inhibition, suggesting that shared inputs are differentially processed in subpopulations resulting in distinct downstream dopamine signals.

Tarfa, Rahilla A; Evans, Rebekah C; Khaliq, Zayd M

Enhanced Sensitivity to Hyperpolarizing Inhibition in Mesoaccumbal Relative to Nigrostriatal Dopamine Neuron Subpopulations Journal Article

In: J Neurosci, vol. 37, no. 12, pp. 3311–3330, 2017, ISSN: 1529-2401.

Abstract | Links

@article{pmid28219982,

title = {Enhanced Sensitivity to Hyperpolarizing Inhibition in Mesoaccumbal Relative to Nigrostriatal Dopamine Neuron Subpopulations},

author = {Rahilla A Tarfa and Rebekah C Evans and Zayd M Khaliq},

url = {https://pubmed.ncbi.nlm.nih.gov/28219982/},

doi = {10.1523/JNEUROSCI.2969-16.2017},

issn = {1529-2401},

year  = {2017},

date = {2017-01-01},

urldate = {2017-01-01},

journal = {J Neurosci},

volume = {37},

number = {12},

pages = {3311--3330},

abstract = {Midbrain dopamine neurons recorded  pause their firing in response to reward omission and aversive stimuli. While the initiation of pauses typically involves synaptic or modulatory input, intrinsic membrane properties may also enhance or limit hyperpolarization, raising the question of how intrinsic conductances shape pauses in dopamine neurons. Using retrograde labeling and electrophysiological techniques combined with computational modeling, we examined the intrinsic conductances that shape pauses evoked by current injections and synaptic stimulation in subpopulations of dopamine neurons grouped according to their axonal projections to the nucleus accumbens or dorsal striatum in mice. Testing across a range of conditions and pulse durations, we found that mesoaccumbal and nigrostriatal neurons differ substantially in rebound properties with mesoaccumbal neurons displaying significantly longer delays to spiking following hyperpolarization. The underlying mechanism involves an inactivating potassium (I) current with decay time constants of up to 225 ms, and small-amplitude hyperpolarization-activated currents (I), characteristics that were most often observed in mesoaccumbal neurons. Pharmacological block of I completely abolished rebound delays and, importantly, shortened synaptically evoked inhibitory pauses, thereby demonstrating the involvement of A-type potassium channels in prolonging pauses evoked by GABAergic inhibition. Therefore, these results show that mesoaccumbal and nigrostriatal neurons display differential responses to hyperpolarizing inhibitory stimuli that favors a higher sensitivity to inhibition in mesoaccumbal neurons. These findings may explain, in part, observations from  experiments that ventral tegmental area neurons tend to exhibit longer aversive pauses relative to SNc neurons. Our study examines rebound, postburst, and synaptically evoked inhibitory pauses in subpopulations of midbrain dopamine neurons. We show that pauses in dopamine neuron firing, evoked by either stimulation of GABAergic inputs or hyperpolarizing current injections, are enhanced by a subclass of potassium conductances that are recruited at voltages below spike threshold. Importantly, A-type potassium currents recorded in mesoaccumbal neurons displayed substantially slower inactivation kinetics, which, combined with weaker expression of hyperpolarization-activated currents, lengthened hyperpolarization-induced delays in spiking relative to nigrostriatal neurons. These results suggest that input integration differs among dopamine neurons favoring higher sensitivity to inhibition in mesoaccumbal neurons and may partially explain  observations that ventral tegmental area neurons exhibit longer aversive pauses relative to SNc neurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

Midbrain dopamine neurons recorded pause their firing in response to reward omission and aversive stimuli. While the initiation of pauses typically involves synaptic or modulatory input, intrinsic membrane properties may also enhance or limit hyperpolarization, raising the question of how intrinsic conductances shape pauses in dopamine neurons. Using retrograde labeling and electrophysiological techniques combined with computational modeling, we examined the intrinsic conductances that shape pauses evoked by current injections and synaptic stimulation in subpopulations of dopamine neurons grouped according to their axonal projections to the nucleus accumbens or dorsal striatum in mice. Testing across a range of conditions and pulse durations, we found that mesoaccumbal and nigrostriatal neurons differ substantially in rebound properties with mesoaccumbal neurons displaying significantly longer delays to spiking following hyperpolarization. The underlying mechanism involves an inactivating potassium (I) current with decay time constants of up to 225 ms, and small-amplitude hyperpolarization-activated currents (I), characteristics that were most often observed in mesoaccumbal neurons. Pharmacological block of I completely abolished rebound delays and, importantly, shortened synaptically evoked inhibitory pauses, thereby demonstrating the involvement of A-type potassium channels in prolonging pauses evoked by GABAergic inhibition. Therefore, these results show that mesoaccumbal and nigrostriatal neurons display differential responses to hyperpolarizing inhibitory stimuli that favors a higher sensitivity to inhibition in mesoaccumbal neurons. These findings may explain, in part, observations from experiments that ventral tegmental area neurons tend to exhibit longer aversive pauses relative to SNc neurons. Our study examines rebound, postburst, and synaptically evoked inhibitory pauses in subpopulations of midbrain dopamine neurons. We show that pauses in dopamine neuron firing, evoked by either stimulation of GABAergic inputs or hyperpolarizing current injections, are enhanced by a subclass of potassium conductances that are recruited at voltages below spike threshold. Importantly, A-type potassium currents recorded in mesoaccumbal neurons displayed substantially slower inactivation kinetics, which, combined with weaker expression of hyperpolarization-activated currents, lengthened hyperpolarization-induced delays in spiking relative to nigrostriatal neurons. These results suggest that input integration differs among dopamine neurons favoring higher sensitivity to inhibition in mesoaccumbal neurons and may partially explain observations that ventral tegmental area neurons exhibit longer aversive pauses relative to SNc neurons.