Scott A. Heldt, Ph.D.
Department of Anatomy and Neurobiology
The University of Tennessee Health Science Center
855 Monroe Ave, Ste 515
Memphis, TN 38163
Phone: (901) 448-2217
Fax: (901) 448-7193
Lab: 532 Link Building
Email: Scott A. Heldt
- Ph.D. Institution: Northern Illinois University
- Postdoctoral: Emory University School of Medicine
Our lab's primary research interest is in understanding the neural mechanisms mediating fear and anxiety in the mammalian brain, with special emphasis focused on GABAergic mechanisms and influences. The results of numerous studies have demonstrated that the amygdala and hippocampus play major roles in neural processes involved in the acquisition, retention, and extinction of conditioned fear. Many of these studies have demonstrated that changes in fast glutamatergic transmission play an important role in the formation of emotional memories associated with the acquisition and extinction of fear. However, there are converging lines of evidence suggesting that changes in GABAergic transmission may also be involved in these processes. One line of our research is designed to examine the role of GABAergic systems in the control of fear in an effort to provide a better understanding of the mechanisms that influence emotional memories and behaviors associated with anxiety and fear.
There is evidence of marked variation in the pharmacological function and regional distribution of specific subtypes of the GABAA receptors in the brain. While recent studies using transgenic mouse lines which possess mutations in various GABAA receptors subtypes have provided important insights into the role of various GABAA receptor subtypes, little is known about the role of subtypes in regionally defined areas of the central nervous system. Thus, our lab is also examines the behavioral and pharmacological function of GABAA receptor subtypes in limbic structures believed to be primary targets for the actions of GABAA receptor ligands. An understand of the role of regional GABAAR function in normal and drug-induced behaviors will advance our understanding of the neural circuitry underlying normal and drug induced behaviors, and may also have direct implications for the development of new strategies for the treatment of disorders treated by subtype-specific ligands.
Our laboratory uses a multidisciplinary approach to examine the molecular and genetic processes influencing fear- and drug-related neural processes including, PCR, in situ hybridization, autoradiography, western blotting, electrophoresis, immunocytochemistry, plasmid cloning, and cutting edge transgenic and viral vector techniques to manipulate the temporal and spatial expression of genes in the brain. In addition, we incorporate a broad variety of behavioral tests useful for investigating experimental manipulations including, the elevated plus maze, Morris water maze, open field apparatus, passive avoidance, drug-induced seizures, light/dark box, forced swim test, horizontal wire test, prepulse inhibition, rotarod apparatus, startle, fear-potentiated startle, and conditioned freezing.
Implications for human anxiety disorders
Anxiety, a generalized sense of apprehension or fear, is normal and perhaps even desirable under certain conditions. However, it can be abnormal when its level is out of proportion to the threat or when it seems inappropriate to the situation. According to the National Institute of Mental Health, the excessive fear of specific objects or in the absence of external threat are hallmarks of a variety of disabling anxiety disorders that affect approximately 40 million American adults during the course of any given year. It seems likely that the fear system of the brain is involved in at least some anxiety disorders, thus the more we understand the details about how the fear circuit works, the better more we will understand how anxiety disorders arise and how they might be prevented or controlled. Given the effectiveness of GABAAR-acting agents and their current widespread use in the treatment of anxiety-related disorders, a fuller understanding of how GABAergic mechanisms control anxiety and fear circuits will advance our understanding of anxiety-related disorders. The lack of therapeutic efficacy may in part be due to a dysfunction of neural processes involved in normal GABAergic reduction or inhibition of fear. Understanding the neural processes involved in both the production and reduction of fear is obviously going to be an important part of understanding how therapy works and why, in some cases, it does not.
- Ogden KK, Khatri A, Traynelis SF, Heldt SA. Potentiation of GluN2C/D NMDA Receptor Subtypes in the Amygdala Facilitates the Retention of Fear and Extinction Learning in Mice. Neuropsychopharmacology. 2013 Sep 6. doi: 10.1038/npp.2013.241. [Epub ahead of print] PubMed PMID: 24008353.
- Pavesi E, Heldt SA, Fletcher ML. Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear learning and increases odor generalization. Learn Mem. 2013 Aug 16;20(9):482-90. doi: 10.1101/lm.031450.113. PubMed PMID: 23955171.
- Heldt SA, Mou L, Ressler KJ. In vivo knockdown of GAD67 in the amygdala disrupts fear extinction and the anxiolytic-like effect of diazepam in mice. Transl Psychiatry. 2012 Nov 13;2:e181. doi: 10.1038/tp.2012.101. PubMed PMID: 23149445; PubMed Central PMCID: PMC3565763.
- Li F, Ryu BY, Krueger RL, Heldt SA, Albritton LM. Targeted entry via somatostatin receptors using a novel modified retrovirus glycoprotein that delivers genes at levels comparable to those of wild-type viral glycoproteins. J Virol. 2012 Jan;86(1):373-81. doi: 10.1128/JVI.05411-11. Epub 2011 Oct 19. PubMed PMID: 22013043; PubMed Central PMCID: PMC3255891.
- Mou L, Heldt SA, Ressler KJ. Rapid brain-derived neurotrophic factor-dependent sequestration of amygdala and hippocampal GABA(A) receptors via different tyrosine receptor kinase B-mediated phosphorylation pathways. Neuroscience. 2011 Mar 10;176:72-85. doi: 10.1016/j.neuroscience.2010.12.041. Epub 2010 Dec 31. PubMed PMID: 21195749; PubMed Central PMCID: PMC3077298.
- Andero R, Heldt SA, Ye K, Liu X, Armario A, Ressler KJ. Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning. Am J Psychiatry. 2011 Feb;168(2):163-72. doi: 10.1176/appi.ajp.2010.10030326. Epub 2010 Dec 1. PubMed PMID: 21123312; PubMed Central PMCID: PMC3770732.