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.
- Gao Y, Heldt SA. Enrichment of GABAA Receptor α-Subunits on the Axonal Initial Segment Shows Regional Differences. Front Cell Neurosci. 2016 Mar 1;10:39. doi: 10.3389/fncel.2016.00039. eCollection 2016. PubMed PMID: 26973458; PubMed Central PMCID: PMC4771769.
- Engin E, Smith KS, Gao Y, Nagy D, Foster RA, Tsvetkov E, Keist R, Crestani F, Fritschy JM, Bolshakov VY, Hajos M, Heldt SA, Rudolph U. Modulation of anxiety and fear via distinct intrahippocampal circuits. Elife. 2016 Mar 14;5. pii: e14120. doi: 10.7554/eLife.14120. PubMed PMID: 26971710; PubMed Central PMCID: PMC4816644.
- Cook MN, Baker JA, Heldt SA, Williams RW, Hamre KM, Lu L. Identification of candidate genes that underlie the QTL on chromosome 1 that mediates genetic differences in stress-ethanol interactions. Physiol Genomics. 2015 Aug;47(8):308-17. doi: 10.1152/physiolgenomics.00114.2014. Epub 2015 May 19. PubMed PMID: 25991709; PubMed Central PMCID: PMC4525077.
- Gao Y, Heldt SA. Lack of neuronal nitric oxide synthase results in attention deficit hyperactivity disorder-like behaviors in mice. Behav Neurosci. 2015 Feb;129(1):50-61. doi: 10.1037/bne0000031. PubMed PMID: 25621792; PubMed Central PMCID: PMC4523066.
- Reiner A, Heldt SA, Presley CS, Guley NH, Elberger AJ, Deng Y, D'Surney L, Rogers JT, Ferrell J, Bu W, Del Mar N, Honig MG, Gurley SN, Moore BM 2nd. Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189. Int J Mol Sci. 2014 Dec 31;16(1):758-87. doi: 10.3390/ijms16010758. PubMed PMID: 25561230; PubMed Central PMCID: PMC4307274.
- Fitzgerald AC, Wright BT, Heldt SA. The behavioral pharmacology of zolpidem: evidence for the functional significance of α1-containing GABA(A) receptors. Psychopharmacology (Berl). 2014 May;231(9):1865-96. doi: 10.1007/s00213-014-3457-x. Epub 2014 Feb 22. Review. PubMed PMID: 24563183.