Abstract
Alcohol dependence and withdrawal has been shown to cause neuroadaptive changes at multiple levels of the nervous system. At the neuron level, adaptations of synaptic connections have been extensively studied in a number of brain areas and accumulating evidence also shows the importance of alcohol dependence-related changes in the intrinsic cellular properties of neurons. At the same time, it is still largely unknown how such neural adaptations impact the firing and integrative properties of neurons. To address these problems, here, we analyze physiological properties of neurons in the bed nucleus of stria terminalis (jcBNST) in animals with a history of alcohol dependence. As a comprehensive approach, first we measure passive and active membrane properties of neurons using conventional current clamp protocols and then analyze their firing responses under the action of simulated synaptic bombardment via dynamic clamp. We find that most physiological properties as measured by DC current injection are barely affected during protracted withdrawal. However, neuronal excitability as measured from firing responses under simulated synaptic inputs with the dynamic clamp is markedly reduced in all 3 types of jcBNST neurons. These results support the importance of studying the effects of alcohol and drugs of abuse on the firing properties of neurons with dynamic clamp protocols designed to bring the neurons into a high conductance state. Since the jcBNST integrates excitatory inputs from the basolateral amygdala (BLA) and cortical inputs from the infralimbic and the insular cortices and in turn is believed to contribute to the inhibitory input to the central nucleus of the amygdala (CeA) the reduced excitability of the jcBNST during protracted withdrawal in alcohol-dependent animals will likely affect ability of the jcBNST to shape the activity and output of the CeA.
Highlights
The neuroadaptive changes associated with alcohol and drug dependence and withdrawal have been a major focus of neuroscience research
We have previously shown that protracted withdrawal from alcohol, cocaine, and heroin as well as chronic intracerebroventricular treatment with corticotropin-releasing factor (CRF) induce common functional adaptations in the jcBNST characterized by the impairment of a form of plasticity of intrinsic excitability [29]
The dynamic clamp experiments allowed us to investigate how the temporal structure of spike responses of jcBNST neurons depended on their intrinsic cellular properties as well as the strength of the simulated synaptic inputs
Summary
The neuroadaptive changes associated with alcohol and drug dependence and withdrawal have been a major focus of neuroscience research. The jcBNST receives robust excitatory efference from the BLA and the amygdalopiriform transition area through the stria terminalis and ansa peduncularis [20,21,22] as well as projections form the dysgranular insular cortex, and the infralimbic cortex [20,22,23,24] and, in turn, sends a major GABAergic projection to the medial part of the central nucleus of the amygdala (CeAm) [23,25]. The jcBNST is well positioned to integrate excitatory inputs form the BLA and dysgranular insular and infralimbic cortical regions and to contribute inhibitory control over the CeA. Changes in the integration properties of jcBNST neurons may contribute to the overall amygdala output and to the persistent emotional dysregulation associated with protracted withdrawal
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