The bed nucleus of the stria terminalis (BNST) plays important roles in the coordination of neuroendocrine, autonomic, somatomotor responses and the effects of drugs of abuse. The juxtacapsular nucleus of the BNST (jcBNST) in the dorsolateral BNST receives dense glutamatergic projections primarily from the posterior part of the BLA and, in turn, sends GABAergic projections to the medial central nucleus of the amygdala (CeAm), the main output nucleus of the amygdala. Thus, changes in the integration properties of jcBNST neurons can contribute to the emotional dysregulation associated with drug dependence and withdrawal. We recently described a form of long-term potentiation of the intrinsic excitability (LTP-IE) of neurons of the jcBNST in response to stimulation of the stria terminalis that was impaired during protracted withdrawal from escalated heroin, cocaine, and alcohol self-administration and in rats chronically treated with corticotropin releasing factor (CRF) intracerebroventricularly. These results provide a novel neurobiological target for vulnerability to drug and alcohol abuse. In particular they suggest the hypothesis that changes in the excitability of jcBNST neurons could result in inadequate inhibition of the CeAm, contributing to the negative affective state that characterizes protracted abstinence in post-dependent individuals. To test this hypothesis here we proposed to 1) investigate changes in synaptic and intrinsic properties of jcBNST neurons associated with heroin dependence using a combination of conventional electrophysiological methods and the dynamic clamp, an innovative computer-based method to study neuronal excitability in brain slices by approximating the high-conductance state of the intact brain;2) to investigate if heroin dependence is also associated with plastic changes in CeAm neurons;3) to use the dynamic clamp to investigate the functional significance of LTP-IE in the BLA-jcBNST-CeA circuit as well as of the plastic changes in jcBNST and CeAm neurons associated with opiate dependence. Ultimately, knowledge of the adaptive and counter-adaptive changes induced by drug dependence in the microcircuit BLA-jcBNST-CeA will allow us to identify therapeutic targets to restore normal neuronal excitability and circuit functioning with adequate inhibitory control over amygdala output.

Public Health Relevance

This project aims to achieve a better understanding of how drug addiction and withdrawal affects neuronal communication in the central nervous system at the levels of single neurons and neural circuits. The results of these studies will advance our understanding of the functional dysregulations of the neural circuits of the extended amygdala that are associated with compulsive drug taking. Ultimately, this project will contribute to the development of novel therapeutic concepts for the therapy of drug abuse, which remains a critical unmet medical need.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Sorensen, Roger
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Scripps Research Institute
La Jolla
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Sz?cs, Attila; Rátkai, Anikó; Schlett, Katalin et al. (2017) Frequency-dependent regulation of intrinsic excitability by voltage-activated membrane conductances, computational modeling and dynamic clamp. Eur J Neurosci 46:2429-2444
Blanchard, Joel W; Eade, Kevin T; Sz?cs, Attila et al. (2015) Selective conversion of fibroblasts into peripheral sensory neurons. Nat Neurosci 18:25-35
Szücs, Attila; Huerta, Ramon (2015) Differential effects of static and dynamic inputs on neuronal excitability. J Neurophysiol 113:232-43
Grieder, Taryn E; Herman, Melissa A; Contet, Candice et al. (2014) VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation. Nat Neurosci 17:1751-8
Szucs, Attila; Berton, Fulvia; Sanna, Pietro Paolo et al. (2012) Excitability of jcBNST neurons is reduced in alcohol-dependent animals during protracted alcohol withdrawal. PLoS One 7:e42313